February 11, 2011 — An additional phase of chemotherapy can counteract higher relapse risks observed in children of Native American ancestry being treated for acute lymphoblastic leukemia (ALL), according to research published online February 6 in Nature Genetics. The new study reported several germline polymorphisms related to ancestry that could alter treatment outcome by influencing drug resistance.
Led by researchers at St. Jude Children's Research Hospital in Memphis, Tennessee, and members of the Children's Oncology Group (COG), the new study was inspired by clinical studies reporting ethnic differences in survival of children treated for ALL.
Researchers analyzed germline single nucleotide polymorphisms (SNPs) in 2534 children of diverse ethnic origin with ALL compared with reference populations — 60 individuals of Northern European, 60 of West African, 90 of East Asian, and 105 of Native American ancestry. Asking "whether genetic ancestry itself was associated with treatment outcome after stratifying for treatment protocols," the study found overall occurrence of relapse associated with greater Native American ancestry (P = .0029).
Patient ethnicity was self-reported; however, further investigation among self-reported white patients found a trend toward higher ALL relapse risk in children with more Native American ancestry (P = .08; n = 1687).
Ongoing analyses divided the patients into those having less than 10% or 10% or higher Native American ancestry. Using this dichotomy, patients were evaluated for relapse risk based on their negative or positive minimal residual disease status after remission induction therapy. Even among patients with negative minimal residual disease, those with 10% or higher Native American ancestry were at greater risk for relapse (P = .006).
This differential relapse risk was absent, however, in patients who received an additional treatment phase — a delayed intensification phase consisting of 8 weeks of treatment with multiple chemotherapeutic agents.
"The term 'delayed intensification' refers to an intensive segment of chemotherapy that is given to patients at a later time point during ALL therapy," explained first author Jun J. Yang, PhD, assistant member, St. Jude faculty, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, by email to Medscape Medical News.
"The purpose is not necessarily to introduce drugs children have not been exposed to before, but rather to give them an extra phase of intensively timed therapy. The benefit is that the extra phase might decrease the risk of relapse," said Dr. Yang. "The con of giving the extra phase...is that it causes some extra toxicity and side effects."
Drugs widely used during the delayed intensification phase are dexamethasone, thioguanine, cyclophosphamide, cytarabine, vincristine, daunorubicin, and asparaginase. A frequently used regimen for remission induction contains the last 3 drugs plus prednisolone.
To understand the role of Native American ancestry, the investigators used genome-wide analyses to identify SNP genotypes associated with risk for relapse, either hematologic or extramedullary. Hematologic relapse risk was most strongly associated with a SNP in gene PDE4B (P = 2.2 × 10−6); this SNP was also associated with relapse risk in general. It was found that primary ALL cells expressing PDE4B more strongly are less sensitive (P = 8 × 10−4) to prednisolone — a component of most remission induction regimens used by St. Jude and COG.
Other loci having genomewide associations between Native American ancestry and ALL relapse risk were found on chromosomes 2 (2p25.3) and 13 (13q32.1).
"PDE4B is the primary regulator of cyclic AMP in lymphoid cells," said Dr. Yang. "Because cAMP is an important messenger molecule, alteration in PDE4B often leads to disruption of important cell functions. In blood cancers, expression of PDE4B is mainly linked to glucocorticoid (prednisolone) response, whereas response to other drugs has yet to be examined."
The authors note that knowledge of genomic variations in the germline holds prognostic value for stratifying relapse risk in patients with ALL. "[G]iving additional chemotherapy can overcome the negative prognostic impact conferred by a set of ancestry-related polymorphisms," they state, "and thereby mitigate ethnic disparities in the outcome of childhood ALL."
Dexamethasone vs Prednisolone
Many groups around the world have moved to using dexamethasone instead of prednisolone for remission induction. In many clinical trials, "dexamethasone has come out as being more effective in preventing relapses than prednisolone," commented Ajay Vora, MD, FRCP, FRCPath, a consultant pediatric hematologist at the University of Sheffield, based at the Sheffield Children's Hospital, United Kingdom, by telephone to Medscape Medical News.
"St. Jude has continued to use prednisolone in induction, as have COG for older patients. There are 2 reasons for that," Dr. Vora explained. "One is that dexamethasone is associated with a higher risk of infections. That can translate into a higher risk of infection-related death — and that is more so in older children.
"And secondly, dexamethasone in the older children is associated with a risk of a bone complication called avascular necrosis," said Dr. Vora. "That is the reason why, despite dexamethasone being found universally to be more effective at preventing relapses, there are variations in its use across the world.
"I think that their study is bringing out a more complicated message, a more subtle message about race and outcome," concluded Dr. Vora. "Ancestry is what determines our genetic make-up, no matter how we might look on the outside.... As long as it's more than 10%, that Native American ancestry within their genome seems to determine their outcome. That is a more complicated and subtle message than just to do with race."
The study was supported by the National Cancer Institute and National Institute of General Medical Sciences of the National Institutes of Health, American Lebanese Syrian Associated Charities, and CureSearch. Support was also provided by the Jeffrey Pride Foundation and the National Childhood Cancer Foundation in the form of funding of genomewide genotyping of COG P9904/9905 samples performed by the Center for Molecular Medicine. One author received grant funding from the American Society of Clinical Pharmacology and Therapeutics Young Investigator Award and Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator. The authors and Dr. Vora have disclosed no relevant financial relationships.
Nat Genet. Published online February 6, 2011.
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