Genetic Variations Associated With Treatment Response for Childhood Leukemia


Children with acute lymphoblastic leukemia with certain genetic variations can have a different response to anti-cancer treatment than other patients, according to a study in the January 28 issue of JAMA.


Pediatric acute lymphoblastic leukemia (ALL) cure rates have increased from less than 10 percent in the 1960s to more than 80 percent today, although considerable unexplained individual variability exists in treatment response, according to background information in the article.


Jun J. Yang, Ph.D., of St. Jude Children’s Research Hospital, Memphis, Tenn., and colleagues conducted a study to identify genetic factors that may affect treatment response in ALL. The researchers tested single nucleotide polymorphisms (SNPs; genetic variations) for their association with minimal residual disease (MRD) at the end of initial chemotherapy in two groups (totaling 487 children) treated for newly diagnosed ALL. Patients were enrolled between 1994 and 2006, with the last follow-up in 2006.


The researchers found that there were 102 SNPs associated with MRD in both groups. All 102 SNPs remained significantly associated with MRD after adjustment for race, sex, leukocyte (a type of blood cell) count at diagnosis, age, and ALL subtype. Of the 102 SNPs, 21 were significantly associated with hematologic (blood-related) relapse. Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. The researchers found that a high proportion (63 of 102 SNPs [61.7 percent]) also were associated with early response, relapse risk, or antileukemic drug disposition.


“Although the acquired genetic characteristics of tumor cells play a critical role in drug responsiveness, our results show that inherited genetic variation of the patient also affects effectiveness of anticancer therapy, and that genome-wide approaches can identify novel and yet plausible pharmacogenetic variation. Such variation may be factored into treatment decisions in the future by placing additional emphasis on optimizing drug delivery to overcome host genetic variation, in addition to the current emphasis on tumor genetic variation,” the authors conclude.


JAMA. 2009;301[4]:393-403.