Survivors of Childhood Leukemia with Down Syndrome Have Unique Health Risks, Benefits

Genetic Condition May Protect Patients from Second Cancers, UCSF Study Shows

By Suzanne Leigh

Doctors have long recognized that children with Down syndrome are significantly more susceptible to leukemia, and have believed that they also were at higher risk of treatment-related chronic conditions. Now, new research led by UCSF Benioff Children’s Hospital San Francisco, with data from the Childhood Cancer Survivor Study, challenges this belief and offers fresh insights into survivorship.

In their investigation, researchers found that, among survivors of childhood leukemia, those with Down syndrome had treatment-related chronic conditions at generally the same rate as survivors without the genetic disorder.

They did find that those with Down syndrome had an increased risk of severe or multiple conditions, including cataracts, hearing loss and thyroid dysfunction. However, when the researchers looked at the onset of these conditions, they determined that they appeared to be less likely related to leukemia treatment, and more likely related to the natural consequences of Down syndrome.

They also found that those in the study with Down syndrome had a significantly decreased risk of second cancers related to their leukemia treatment.

The findings were published in the journal Cancer on Nov. 3, 2017.

The researchers, led by Robert Goldsby, MD, of UCSF Benioff Children’s Hospital San Francisco, tracked the outcomes of 154 pediatric leukemia survivors with Down syndrome, a disorder caused by an extra copy of chromosome 21. They compared them with 581 non-Down syndrome survivors, matched by age at diagnosis, race, gender and treatment. Both groups had a minimum of five years’ survivorship. Approximately two-thirds of survivors had been diagnosed with leukemia between the ages of 1 and 4, and the majority were aged between 10 and 29 at the time of last follow-up.

The study participants had been diagnosed with acute lymphoblastic leukemia (ALL), the most common pediatric cancer, or acute myeloid leukemia (AML), which together make up about 30 percent of all childhood cancers.

Risks May Be ‘Natural History’ of Down Syndrome

The overall survival at 25 years post-diagnosis was similar in both groups: 88 percent for those with Down syndrome, versus 84 percent for those without.

While survivors with Down syndrome were at higher risk of certain chronic health conditions, these had been apparent prior to or in the early years following diagnosis, suggesting they may reflect the “natural history” of Down syndrome. When the researchers looked at chronic conditions occurring at least five years after diagnosis, the rates were similar for both groups: 20 percent for the Down syndrome group, versus 16.5 percent for the non-Down syndrome group.

The researchers noted that, historically, the risks of chronic conditions for the Down syndrome survivors may have been inflated. “The patients’ chronic health conditions were usually reported by their parents,” said Goldsby of the UCSF Department of Pediatric Hematology/Oncology. “We know from previous studies that parents are more concerned about future health and late effects than patients, and are more likely to over-report events.”

“Nevertheless, we cannot exclude the possibility that treatment for childhood leukemia might exacerbate or increase the risk for some of these conditions,” said senior author Wendy Leisenring, ScD, of the Fred Hutchinson Cancer Research Center in Seattle. “It is possible that children with Down syndrome and underlying heart disease may not have survived the required five years to be eligible for the study.”

Regarding the incidence of second cancers in the Down syndrome survivors, the researchers found a single case (0.6 percent), versus 26 cases (4.3 percent) in the non-Down syndrome group.

“The lower risk of second cancers may indicate a potential protective effect of one or more chromosome 21-localized genes,” said Goldsby, who is the medical director of the UCSF Childhood Cancer Survivors Program. “Studies assessing genetic and environmental modifiers that may influence these risks are warranted.”

Kids with Down Syndrome Twice as Likely to Survive AML

Previous studies have shown that Down syndrome patients are less likely to survive ALL than non-Down syndrome patients, but are more than twice as likely to survive AML – approximately 80 percent, compared with 35 percent – due to a genetically distinct form of AML that may be more sensitive to chemotherapy. Down syndrome survivors of both types of leukemia are more likely to suffer from acute toxicities relating to chemotherapy, such as mucositis, sepsis and pulmonary complications.

Children with Down syndrome face a 2-3 percent overall risk of developing AML or ALL, according to the American Cancer Society. Among the general pediatric population in the United States, approximately 3,500 are diagnosed with leukemia each year, or about a 0.0052 percent rate overall.

The study was supported by funding from the National Cancer Institute, Alex Lemonade Stand Foundation, Swim Across America, Cancer Center Support and the American Lebanese-Syrian Associated Charities (ALSAC). Co-author Charles Sklar, MD, declared that he has received honoraria from EMD Serono, Inc.

Co-authors are Shannon Raber and the late Arthur Ablin, MD, of UCSF; Kayla Stratton of Fred Hutchinson Cancer Research Center in Seattle; Louise Strong, MD, of MD Anderson Cancer Center in Houston; Kevin Oeffinger, MD, and Charles Sklar, MD, of Memorial Sloan-Kettering Cancer Center in New York; Gregory Armstrong, MD, principal investigator of the  Childhood Cancer Survivor Study, and Leslie Robison, PhD, of St. Jude Children’s Research Hospital in Memphis; and Smita Bhatia, MD, of Children’s Hospital of Alabama in Birmingham.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.