Advances in Pediatric Oncology

In 2013, Lisa Giulino Roth, MD, was newly married and had just finished a fellowship in pediatric hematology/oncology when she was diagnosed with stage II Hodgkin lymphoma. Dr. Giulino Roth, who is now Director of Pediatric Oncology at NewYork-Presbyterian Komansky Children’s Hospital, completed a four-month course of chemotherapy and has been in remission since. That life-changing experience prompted Dr. Giulino Roth just one year later to establish the Adolescent and Young Adult Lymphoma Program at Weill Cornell Medicine to help teens and young adults navigate the intricate medical, personal, and psychosocial issues that accompany a lymphoma diagnosis.

Dr. Lisa Giulino Roth

“I wanted to create a program that addresses the special needs of a young person with a cancer diagnosis,” says Dr. Giulino Roth. “These patients can fall through the cracks. They often feel lost – not quite fitting into the pediatric clinic, but not the adult clinic either. A patient might see a pediatric oncologist or a medical oncologist and receive vastly different treatment for the exact same diagnosis.”

Each year, nearly 90,000 adolescents and young adults ages 15 to 39 years are diagnosed with cancer. “The spectrum of cancers that are seen in adolescents and young adults, termed ‘AYAs’ by the National Institutes of Health, is quite different than the spectrum you see in either pediatrics or in older adults,” says Dr. Giulino Roth. “The most common malignancy is lymphoma, representing 20 percent of the cases, the bulk of which are Hodgkin lymphoma.”

Despite important advances in cancer care leading to excellent outcomes in childhood and adult lymphoma, improvements in survival among AYAs have fallen behind. According to Dr. Giulino Roth, this may be due in part to delayed diagnosis, inconsistency in treatment and follow-up, low rates of enrollment in clinical trials, potential differences in disease biology, psychosocial challenges, and disparities in access to health insurance.

Adolescents and young adults with lymphoma may encounter challenges different from those of their younger and older adult counterparts, including the effects of cancer treatment on fertility, the strains placed on young adults who may be newly independent and facing a life-threatening illness, and navigating a diagnosis and treatment throughout school or work. This complex set of needs necessitates a specialized multidisciplinary approach to care. Under Dr. Giulino Roth, the AYA Lymphoma Program brings together specialists in medical, surgical and radiation oncology and bone marrow and stem cell transplantation. Additionally to manage the concerns of this population, the program provides physicians with expertise in reproductive medicine and fertility preservation. A dedicated social worker also helps patients confront psychosocial challenges, while art, life, and integrative therapies assist in problem solving, reducing stress, and increasing self-esteem.

“Studies have shown that AYA lymphoma survivors have significant quality-of-life impairments, including physical, cognitive, and emotional difficulties as well as fatigue and financial concerns,” adds Dr. Giulino Roth. “Therefore, it is imperative that providers are keenly aware of both the clinical and emotional impact of a lymphoma diagnosis and treatment in the AYA population and provide appropriate referral for both medical and social/psychological support. Comprehensive, multidisciplinary, and patient-centered AYA clinical care models represent the ideal setting to provide developmentally appropriate care to this population both during cancer treatment and long-term survivorship follow-up.”

In the February 2021 issue of Current Hematological Malignancy Reports, Dr. Giulino Roth provides a comprehensive review of AYA considerations in the treatment of Hodgkin lymphoma and primary mediastinal B-cell lymphoma. The article addresses the current knowledge about disease in AYAs, adult and pediatric treatment strategies, novel targeted therapies, ongoing AYA clinical trials in the lymphoma subtypes, considerations for treatment-related toxicities in AYAs, as well as psychosocial issues specific to this population.

Targeting the Distinct Treatment Challenges

“Our robust clinical trials portfolio at NewYork-Presbyterian and Weill Cornell Medicine provides our patients with access to novel, practice-changing therapies often not available elsewhere and can help uncover innovative ways to manage and/or prevent potential long-term complications of treatment,” says Dr. Giulino Roth.

Pediatric and adult trials in Hodgkin lymphoma and primary mediastinal B-cell lymphoma, a non-Hodgkin lymphoma that has a peak incidence in the AYA population, have demonstrated that treatment with dose-intense chemotherapeutic regimens with or without radiation results in high cure rates but can also be associated with long-term toxicity.

“Primary mediastinal B-cell lymphoma is a rare subtype of lymphoma that disproportionately affects females. The large masses in the chest have traditionally been treated with chemotherapy and radiation, but there is a lot of effort to decrease reliance on radiation,” notes Dr. Giulino Roth, who is Principal Investigator of a phase 3 multicenter trial on immunotherapy with the monoclonal antibody nivolumab funded by the National Cancer Institute and Children’s Oncology Group. “We have brought together national cooperative groups in pediatrics and adults for a single trial to study a new addition to standard chemotherapy, allowing patients to be treated with chemotherapy and a novel agent with less reliance on radiation.”

Informing Potential Therapies in the Laboratory

In March 2022, the Starr Cancer Consortium, a collaboration among five leading research institutions – Weill Cornell Medicine, the Broad Institute of MIT and Harvard, Cold Spring Harbor Laboratory, Memorial Sloan Kettering Cancer Center, and The Rockefeller University – awarded Dr. Giulino Roth and her research team a grant to apply new technologies in developing more detailed knowledge of tumor biology in Hodgkin lymphoma. “Historically, this has been very difficult to study because tumor cells are extremely rare in the mass itself. We are working to understand the biology differences between children and adults and the genetic alterations in Hodgkin lymphoma,” she says.

The Weill Cornell Medicine researchers will seek to define the evolution and tumor microenvironment interactions of classic Hodgkin lymphoma through single-cell multi-omics and genetically engineered mouse models. Current treatments for classic Hodgkin lymphoma often cause long-term side effects, but a lack of good laboratory models for the disease has hindered efforts to develop better therapies. One major problem is that a small minority of cells in the Hodgkin tumor microenvironment drive the disease, and the activities of these cells are hard to detect with bulk gene sequencing methods.

Dr. Giulino Roth’s team previously developed novel cell-sorting techniques to isolate the tumor-driving cells, analyzing their unique genomes and gene expression profiles. That work revealed a complex tumor, with extensive interactions between the Hodgkin Reed Sternberg cells and non-malignant cells in the tumor microenvironment. With the Starr Cancer Consortium’s support, the researchers now plan to trace the lineages of these different cell types to determine how they arose within the tumor and build new mouse models of the disease.

“We’ve learned that younger patients had more genetic mutations than older patients, which is counterintuitive. We are trying to understand why that might be and what genetic alterations or drugs could be developed to target early events at very early timepoints,” says Dr. Giulino Roth. “If we are successful, we can understand which drugs to prioritize in treating the disease.”