St Jude Hospital. US: Researchers have identified the first genetic variation that is
associated with increased risk and severity of peripheral neuropathy
following treatment with a widely used anti-cancer drug. Investigators
also found evidence of how it may be possible to protect young leukemia
patients without jeopardizing cures. St. Jude Children’s Research
Hospital scientists led the study, which appears today in the Journal of the American Medical Association.
The study involved 321 children and adolescents whose acute
lymphoblastic leukemia (ALL) treatment included between 36 and 39 doses
of the drug vincristine.
Researchers screened patient DNA for almost 1 million common
inherited genetic variations and found that 60.8 percent of those who
inherited two copies of a variation in a gene named CEP72
developed peripheral neuropathy. Vincristine-related peripheral
neuropathy was diagnosed in 23.4 percent of patients who inherited at
least one of the more common versions of CEP72. Patients with two copies of the high-risk CEP72
variant were also more than twice as likely as other patients to
experience serious, disabling or life-threatening peripheral neuropathy.
The newly identified CEP72 variant also increased the
sensitivity of cancer cells to vincristine. “That suggests it might be
possible to lower the vincristine dose in these patients without
compromising the likelihood of cures,” said the corresponding author
William Evans, Pharm.D., a member of the St. Jude Department of
Pharmaceutical Sciences. The possibility will be studied in a St. Jude
clinical trial scheduled to open later this year for newly diagnosed
pediatric ALL patients.
“St. Jude researchers have already achieved high cure rates for ALL.
In this study, they identified a possible reason why some people
experience a serious side effect of the medication—debilitating nerve
pain,” said Rochelle Long, Ph.D., director of the National Institutes of
Health Pharmacogenomics Research Network. “This genetic insight will
help scientists devise treatment plans that ensure safety and
effectiveness as well as the long-term quality of life for children with
ALL.”
Vincristine is one of the most widely used and effective agents for
treatment of leukemia, lymphoma, brain and solid tumors in children and
adults. But in a significant number of children and adults, the drug
causes episodes of peripheral neuropathy that can become chronic and
resurface in adulthood. The symptoms, which include pain, numbness and
other changes that make walking difficult, are often severe enough to
delay treatment. Such delays can compromise the likelihood of a cure.
Currently there is no way to identify patients who are most likely to
develop the nerve damage.
Overall 50 patients, or 16 percent of 321 those in this study, inherited two copies of the high-risk CEP72
variant. The study included 222 newly diagnosed patients enrolled in
the St. Jude Total XIIIB clinical trial between 1994 and 1998. The
remaining 99 patients were part of a Children’s Oncology Group (COG)
study for relapsed patients. COG is the world’s largest organization
devoted exclusively to childhood and adolescent cancer research.
The high-risk CEP72 variant identified in this study was
linked to a greater risk of peripheral neuropathy even when researchers
took other risk factors into account, including race and vincristine
dose. Vincristine-related peripheral neuropathy is less common among
African-American patients. Researchers found that the high-risk version
of the gene is also less common in African-American patients, so they
are less likely than patients from other racial backgrounds to inherit
the high-risk version of CEP72.
CEP72 carries instructions for assembling the CEP72
protein, which is essential for formation of the cellular machinery
that ensures genetic material is divided properly during cell division.
Vincristine targets the same process in cells.
The high-risk CEP72 variation occurs in a region of DNA that
regulates gene activity and turns the gene on and off. In cells growing
in the laboratory, investigators showed the high-risk variant was
associated with reduced CEP72 activity and greater sensitivity to vincristine in human nerve cells and cancer cells, including ALL.
Evans and his St. Jude colleagues have pioneered the use of
pharmacogenetics to enhance the safety and effectiveness of chemotherapy
by studying how inherited differences in the makeup of genes influence
patients’ response to drugs. “Today at St. Jude, 94 percent of newly
diagnosed ALL patients will be alive in five years,” Evans said. “The
challenge now is to maintain and improve cure rates while improving the
quality of life for children during treatment and beyond.”
The study’s first author is Barthelemy Diouf, of St. Jude. The other
authors are Kristine Crews, Deqing Pei, Cheng Cheng, Ju Bao, Jie Zheng,
Wenjian Yang, Yiping Fan, Steven Paugh, Joseph McCorkle, Ching-Hon Pui
and Mary Relling, all of St. Jude; Glen Lew, Emory University, Atlanta;
Heather Wheeler, Claudia Wing, Shannon Delaney, Masaaki Komatsu and M.
Eileen Dolan, all of University of Chicago; Xiaomin Lu and Meenakshi
Devidas, both of University of Florida, Gainesville; Naomi Winick,
University of Texas Southwestern School of Medicine, Dallas; William
Carroll, New York University Cancer Institute; Mignon Loh, University of
California School of Medicine, San Francisco; and Stephen Hunger,
University of Colorado School of Medicine, Children’s Hospital Colorado,
Aurora.
The study was funded in part by grants (CA36401, GM92666, GM61393,
CA136765, CA165823, CA21765, CA98543, CA98413, CA114766) from the
National Institutes of Health and by ALSAC.
St. Jude Media Relations Contacts
Carrie Strehlau
desk (901) 595-2295
cell (901) 297-9875
carrie.strehlau@stjude.org
Summer Freeman
desk (901) 595-3061
cell (901) 297-9861
summer.freeman@stjude.org