BIG STEPS FOR OUR LITTLEST PATIENTS

By Jane Kollmer

A cancer diagnosis can be devastating for a child and their family, but there is cause for hope. Fifty years ago, the survival rate was less than 10%. However, major advances over the past few decades have led to greatly improved outcomes, with over 85% of children diagnosed with cancer becoming long-term survivors.

Ami V. Desai, MD, MSCE

Despite a 71% decrease in cancer death rates for children from 1970 through 2019, cancer remains the leading cause of death from disease among this age group. According to the latest statistics, in 2022 an estimated 10,470 new cases of cancer will be diagnosed in the United States among children from birth to 14 years, and about 1,050 children are expected to die from the disease. The experienced team of pediatric cancer specialists at the University of Chicago Medicine Comer Children’s Hospital provides the most advanced care available to more than 3,000 young people each year. They diagnose and treat children with common and rare forms of cancer. The staff’s high level of expertise and skill allows them to take on the most challenging cases that may be considered too difficult to treat at other pediatric hospitals. Progress in treatment and prognosis for pediatric cancer is partly due to investment in laboratory science and clinical research. Almost 75% of children with cancer are enrolled on clinical trials, which is far more than in adults with cancer. This gives researchers more opportunities to learn from the study results. As a member of the Children’s Oncology Group (COG), the national cooperative group studying childhood cancers, UChicago Medicine physicians frequently collaborate with other leading pediatric oncologists from around the world to identify better ways to diagnose and treat childhood cancers. In fact, Comer Children’s offers one of the largest and most comprehensive portfolios of pediatric cancer clinical trials. “At any one time, there are more than 80 cancer clinical trials available to young patients at Comer Children’s,” said Tara O. Henderson, MD, MPH, Arthur and Marian Edelstein Professor of Pediatrics, Section Chief, Pediatric Hematology, Oncology and Stem Cell Transplantation at Comer Children’s Hospital. “Because of the innovative research conducted here, our patients often have access to new treatments years before they are widely available elsewhere.” UChicago Medicine is a member of the Pediatric Early Phase-Clinical Trial Network, which serves as a national and international model for new agent development in pediatric oncology. This dedicated consortium provides the necessary infrastructure for the conduct of pediatric early phase clinical trials and pharmacokinetic and biomarker studies. Ami V. Desai, MD, MSCE, assistant professor of pediatrics, is an expert in conducting early phase (phase 1) clinical trials, studies that investigate and develop novel treatments for childhood cancers. These small-sized studies are critical as they test the safety, side effects, best dose and timing of a new treatment. Desai has helped greatly to expand UChicago Medicine’s portfolio of phase 1 studies. She uses pharmacology and biomarker data to explore new therapies for solid tumors. Through this research, she is examining how the body reacts to drug treatments in order to reduce toxicity, improve patient response to medication and enhance overall health outcomes. Larger studies are instrumental in finding out if new treatments are better than existing ones and may lead to a new standard of care. For example, Jennifer McNeer, MD, associate professor of pediatrics and director of the pediatric leukemia program, is co-chair of a COG trial (AALL1732, NCT03959085) for children and young adults with high-risk B-cell acute lymphoblastic leukemia (B-ALL). This randomized, phase 3 trial is enrolling nearly 5,000 patients to understand if adding an immunotherapy drug called inotuzumab to the standard-of-care chemotherapy regimen maintains or improves outcomes in patients with newly diagnosed disease.

“Given our experience in recent trials that suggests we are at the limits of what we can do with conventional cytotoxic chemotherapy agents to improve outcomes in B-ALL, as well as the promising results with immunotherapies in patients with relapsed/refractory disease, it is exciting to be moving effective immunotherapy agents to frontline therapy,” said McNeer.

The lack of data and samples for study have been the most significant barriers to large-scale discovery and advancement in the treatment of pediatric cancers. The field of bioinformatics is addressing this problem with infrastructure that makes it easier for physicians worldwide to share data and work collaboratively.

UChicago Medicine is one of the sites that the Leukemia & Lymphoma Society is partnered with to develop an integrated multi-site, multitherapy master clinical trial with the goal of matching patients to precision treatment based on their unique tumor biology. This new model, called LLS PedAl, aims to create operational and cost efficiencies in study management, make data from different sources interoperable, facilitate easy identification of appropriate patients for new therapies, and consolidate clinical and scientific data from academic medical centers and cooperative groups across the United States and Europe. To achieve its goals, LLS PedAL requires a robust data infrastructure that supports a wide variety of research and clinical activities, including harmonization of historical data and data mining to match patients to clinical trials. In addition to testing numerous targeted therapies, LLS PedAL will consolidate pediatric cancer data from all sites into a single data set known as the Pediatric Cancer Data Commons (PCDC). Pediatric oncologist Sam Volchenboum, MD, PhD, MS, director of the PCDC, is leading the bioinformatics component of LLS PedAL and is developing and deploying the two-part data platform on which the pilot project will run. “We are so excited to be building the next-generation platform for matching children with leukemia to innovative clinical trials,” Volchenboum said. “In the process, we will be creating the largest pediatric leukemia data set in the world.”

Maya Gray was just 8 years old when a routine blood test uncovered a problem with her white blood cells. She was eventually diagnosed with acute lymphoblastic leukemia (ALL), a quickly progressing and potentially deadly cancer of the blood and bone marrow. What followed was 27 difficult months of chemotherapy, spinal taps and a complication that had her using crutches for a short time. While the treatment plan recommended by her team at University of Chicago Medicine Comer Children’s Hospital wasn’t easy, it cured her cancer. Today, 11 years later, the girl nicknamed “Miracle Maya” remains cancer-free.

University of Chicago Medicine Comer Children’s Hospital

Neuroblastoma is a type of cancer that forms from immature nerve cells most often found in children younger than 5 years of age. According to the National Cancer Institute, about 800 children are diagnosed with neuroblastoma each year in the United States. It is the most common nonbrain solid tumor that often forms in and near the abdomen and in the chest or neck region along the spine. About half of kids diagnosed with neuroblastoma are considered to have high-risk neuroblastoma, meaning that their cancer is particularly aggressive and difficult to treat. For many years, high-risk neuroblastoma was considered to be nearly incurable. Because it is so aggressive and can rapidly prove fatal, developing treatments that can prevent or delay relapse has been a high priority. Led by Susan Cohn, MD, professor of pediatrics and an international authority on this childhood cancer, researchers at UChicago Medicine are conducting clinical trials for the disease, including phase 1 trials for aggressive, relapsed neuroblastoma. Desperately needed are new biomarkers to distinguish children who are likely to respond to standard treatments for neuroblastoma from those who may benefit from alternative approaches. Mark Applebaum, MD, assistant professor of pediatrics, and his team are studying a new method to find cancer DNA in blood samples, known as “liquid biopsies.” He is developing a robust test using routine blood samples to follow the disease and predict which patients will respond to standard treatment and which patients are resistant to standard therapy and may benefit from changes in treatment. Applebaum hopes to develop biomarkers to improve risk stratification at diagnosis, biomarkers of minimal residual disease for early therapy intervention, and the identification of gene networks which drive high-risk neuroblastoma. This work will have a transformative impact by identifying new ways to diagnose and monitor neuroblastoma using liquid biopsies, potentially enabling early introduction of novel therapeutics. This project will lead to novel blood tests that will provide vital information for optimizing treatments for each patient to improve outcomes. Such a personalized approach is the holy grail for allowing more children to receive just the right amount of treatment with fewer side effects. “We envision that our test will allow us to move away from a one-size-fits-all approach to treating neuroblastoma,” said Applebaum. “In the shortand medium-term, we expect to be able to rapidly identify children who are not responding to conventional chemotherapy and may benefit from novel approaches.”

In 2018, three Chicago-area health systems came together to form a network of pediatric clinical services called the Chicagoland Children’s Health Alliance (CCHA). Through this collaboration between the University of Chicago Medicine Comer Children’s Hospital, Advocate Children’s Hospital and pediatrics at NorthShore University HealthSystem, more children have gained increased access to care across the areas of pediatric cancer and blood diseases; cardiology and cardiac surgery; gastroenterology; neurology and neurosurgery; and general pediatric surgery.

Not only does this expand current expertise to more children, but also the organizations are working together to strengthen clinical capabilities and promote new programs and innovative therapies. In addition, the institutions are enhancing the coordination of academic research to improve patient outcomes, as well as to train the next generation of physicians. “By partnering on these important pediatric services, we are building a stronger and more diverse network of care,” said John M. Cunningham, MD, George M. Eisenberg Professor and chair of the Department of Pediatrics and physician-in-chief of Comer Children’s Hospital. “We are tapping physicians with strong national reputations in their fields to help lead our collective efforts.” Specifically, the integrated and comprehensive system of pediatric experts — from primary care to highly specialized care, as well as expertise in maternal and fetal medicine — will now be accessible to families living near a geographic region that spans Chicago and its suburbs and Northwest Indiana. Clinical sites include Hyde Park, Chicago, Evanston, Wilmette, Park Ridge, Oak Lawn, Tinley Park, Naperville and Merrillville, Indiana. “The CCHA’s goal is to support patients’ and families’ needs for the highest level of pediatric care with easier access to pediatricians and pediatric specialists at a lower cost,” explained Tara O. Henderson, MD, who is the chief of the CCHA’s Cancer and Blood Disorders Service Line. Since its formation in 2018, the CCHA has been working together to share and adopt the best practices for patients; provide seamless referrals and ongoing coordinated care for children; and develop and apply new innovations and technologies to improve the patient experience.

Survivors of childhood cancer need specialized care as they age. The toxic treatments they received may have a negative impact on their health later in life. For children who receive cancer treatments, any developing organ can be impacted by chemotherapy and radiation. That puts them at risk for developing heart failure and lung disease, along with secondary cancers. Because of this, their health needs to be monitored to proactively prevent and treat any long-term issues associated with cancer therapy.

Tara O. Henderson, MD, directs the Childhood Cancer Survivor Center at the University of Chicago Medicine Comer Children’s Hospital — one of the preeminent academic childhood survivorship programs in the nation. There, she works with childhood cancer survivors to understand their risk of second cancers and the longterm health consequences of cancer therapy.

“We see survivors of both childhood and young adult cancers, providing them with ongoing surveillance and interventions to ensure any new problems are caught early,” said Henderson. “Importantly, that includes having open communication with cancer survivors’ primary care doctors, who are often unaware of the ongoing risks in this population.” In addition, Henderson’s research program is dedicated to understanding the types and frequencies of second cancers that arise in these survivors and how best to care for them in the long term. She is the principal investigator of two National Cancer Institute-funded intervention trials to improve screening and early detection of secondary cancers in adult survivors of childhood cancer. Female childhood cancer survivors — even if they did not receive radiation treatments to their chest — are six times more likely than the general population to be diagnosed with breast cancer. For those who did receive chest radiation, that chance increases exponentially and is on par with those who have the BRCA1 or BRCA2 genetic mutations. The ultimate goal is to minimize the health effects and identify diseases like breast cancer early. Henderson and colleagues recently published in JAMA Oncology a study of 11,550 female survivors of childhood cancer finding that ongoing efforts to both improve survival outcomes and minimize longterm toxic effects of treatment were associated with a decreased risk of breast cancer over time. Since outcomes in this population are similar to breast cancer outcomes in the general population, diagnosing breast cancer when it is stage 1 often leads to a greater than 90% cure rate. “We want survivors to stay engaged throughout their lifetimes and know that once they are cured, they still need to know their risks,” said Henderson. “That doesn’t necessarily mean they will have issues, but we want them to be empowered with information and not get lost in follow-up.”