Improving Leukemia Care for Children with Down Syndrome

Children with Down syndrome have approximately a 20-fold increased risk of developing leukemia compared with other children. These patients have also historically experienced poorer outcomes and increased complications when treated with standard protocols for acute lymphoblastic leukemia (ALL). At UCSF Benioff Children’s Hospitals, ranked as one of the nation's top 10 hospitals for pediatric cancer care by U.S. News & World Report, specialists are working to change outcomes for these patients through groundbreaking research and clinical trials.                                                                                                               

Karen Rabin, MD, PhD, pediatric hematologist-oncologist and director of the Pediatric Leukemia Program at UCSF Benioff Children’s Hospitals, is at the forefront of leukemia and Down syndrome research. Rabin is working to uncover the causes of these complications and identify therapies that may yield better results for patients.

Using immunotherapy for ALL

“Children with Down syndrome don’t tolerate intensive chemotherapy as well as other children,” says Rabin. “They experience more infectious complications, and the toxicity burden from traditional chemotherapy is significant. Immunotherapy is a promising alternative that harnesses the immune system to attack and destroy the leukemia cells, instead of relying exclusively on chemotherapy.”

Rabin served as vice chair of a recently completed Children's Oncology Group (COG) study that enrolled more than 4,000 patients with newly diagnosed B-cell ALL. The study evaluated whether adding blinatumomab, a potent immunotherapy drug that has revolutionized childhood ALL treatment, could improve outcomes compared with standard chemotherapy alone.

Patients who received blinatumomab had improved disease-free survival and reduced rates of relapse. Importantly, children with Down syndrome showed a similar pattern of benefit from treatment with blinatumomab as other children enrolled in the study. They did not experience significantly more side effects, unlike their vulnerability to severe side effects of chemotherapy. “We are hopeful that immunotherapy will move the needle and lead to better outcomes for children with Down syndrome,” Rabin says.

Rabin is building on these results as co-chair of the next COG trial being planned for high-risk ALL in children with Down syndrome. This phase 2 study will incorporate both blinatumomab and a second highly promising form of immunotherapy, inotuzumab ozogamicin. “We hope this new innovative regimen using more immunotherapy and less chemotherapy will improve cure rates without the severe side effects that we have seen with chemotherapy-based treatment regimens,” Rabin explains.

Exploring the root cause of chemotherapy complications

Rabin and fellow researchers are also working to understand why some children with Down syndrome experience severe infections during leukemia treatment. Her R01-funded study is analyzing data from approximately 200 children with Down syndrome treated for ALL.

The team is evaluating genetic variants in immune-related pathways that may influence drug metabolism and immune function. “We hope to identify which patients have genetic variants that predict a high risk of infection before they start therapy,” says Rabin. “With this information, we can take steps to reduce complications and tailor the treatment to their needs.”

Possibilities for earlier treatment and prevention

Rabin is also a co-investigator on an NIH-funded U01 program project, the DECODE (Down syndrome Early Childhood Omics, Deep phenotyping, and Epidemiology) Study. This large-scale longitudinal cohort study will follow 1,000 children with Down syndrome from birth, providing comprehensive assessments at regular intervals throughout childhood.

The study, launched in 2024 and set to continue until at least 2029, aims to identify early biomarkers and risk factors for leukemia development. “The DECODE study could potentially open doors to leukemia prevention strategies or earlier intervention,” says Rabin.

New strategies for ML-DS relapse

While much of Rabin's work focuses on ALL, she also treats and studies myeloid leukemia of Down syndrome (ML-DS). This unique form of acute myeloid leukemia occurs exclusively in children with Down syndrome before age 4 and is characterized by mutations in the GATA1 gene.

“ML-DS has much better outcomes than other forms of AML in young children,” Rabin notes. “However, outcomes at relapse are extremely poor, so our focus is on further optimizing frontline therapy to prevent relapse in the first place.”

Another factor to consider is transient abnormal myelopoiesis (TAM), which occurs in 20% to 30% of newborns with Down syndrome. The features of TAM are difficult to distinguish from leukemia, but remarkably, it usually resolves without requiring chemotherapy. However, about 25% of affected infants will go on to develop ML-DS by age 4.

“Careful monitoring is essential, even after TAM resolves,” Rabin says. Children with both TAM and ML-DS should see an experienced clinician to ensure a detailed diagnosis and the best treatment plan. The UCSF team has extensive experience in diagnosing and managing these rare conditions.

A fulfilling mission

For Rabin, this work addresses persistent disparities in pediatric cancer outcomes. This research-to-bedside approach is central to UCSF’s mission, where patients benefit from innovative therapies and the expertise of specialists dedicated to pediatric blood cancers. “It’s really gratifying, feeling like we are making headway with developing improved treatments,” she says. “The families are incredibly inspiring, and seeing these children thrive makes this work deeply rewarding.”

She’s optimistic about the future of pediatric cancer care. “It’s a really promising time,” she says. “The field of pediatric oncology is always pushing forward and identifying new strategies to improve our patients’ outcomes.”