Personalized strategies critical for childhood cancer

Genomic tools are helping to guide the search for new insights into uncommon childhood cancers like pediatric Acute Myeloid Leukemia (AML) and lymphomas - insights that, researchers hope, will improve survival rates and better spare survivors of childhood cancers from long-term treatment-associated health effects in adulthood, according to experts who spoke Saturday, December 5  at the 57^th American Society of Hematology (ASH) Annual Meeting.

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Most newly-diagnosed childhood cancers are acute lymphoblastic leukemias (ALL). But myeloid malignancies - those affecting the red blood cells - represent 20% of childhood leukemias, and these, along with Hodgkin and non-Hodgkin lymphomas, account for 15% of all malignancies diagnosed before age 14 years in the United States, said E. Anders Kolb, MD. He is director, Blood and Bone Marrow Transplant Program, Nemours Center for Cancer and Blood Disorders, Alfred I. duPont Hospital for Children in Wilmington, Del.

Myeloid malignancies and lymphomas are often referred to as the “other” childhood cancers, he said.

Dr. Kolb

Despite advances, children diagnosed with acute myeloid leukemia (AML) suffer “a considerable survival gap,” Kolb noted. “As a result, these cases contribute significantly to childhood cancer mortality.”

In contrast, pediatric and adolescent Hodgkin lymphoma “is one of the most curable forms of childhood cancer,” noted Kara M. Kelly, MD, pediatric oncologist, Department of Pediatrics, Division of Pediatric Hematology/Oncology/Stem Cell Transplantation department, Columbia University Medical Center, in New York, N.Y. The challenge these patients face is that their long-term survival rates decline in adulthood because of long-term side effects like secondary cancers and cardiovascular disease, resulting from cancer treatment in childhood.

As a result of these chronic-disease-associated premature deaths among long-term survivors, Hodgkin Lymphoma has one of the highest societal burdens of cancer, in terms of lost productivity, Kelly noted. “This impacts not only the individual patient, but society as a whole,” she said.

Dr. KellyIn the era of precision medicine, however, Kolb and Kelly are hopeful that next-generation gene sequencing and biomarkers can help identify ways to address both challenges, improving survival rates and reducing toxicities for children with these “other” pediatric cancers.

“The major challenge is to optimize the balance between overall survival and treatment-related toxicity,” said Kelly. “Despite our good overall survival rates, there really is no standard of care or stratified-risk strategy for pediatric Hodgkin [Lymphoma].”

There is no consensus about chemotherapy or radiotherapy strategies, imaging standards are outdated and lacking evidence, and the underlying biology is “not yet advanced enough to guide treatment,” she lamented.

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But there are glimmers of hope. Advanced imaging assessments of treatment response using computed tomography (CT) and positron-emission tomography (PET) are being developed with the hope that children who respond rapidly to therapy can be directed to less-toxic treatments or lower doses, notes Kelly.

And with the arrival of next-generation gene sequencing and other advanced technologies for personalized medicine, she is also hopeful that biomarkers will soon be found not only for treatment response, but markers of long-term toxicity risks.

“The goal is to use a classifier to develop personalized approaches that balance tumor control with acute and long-term toxicities,” she explained. But the low prevalence of these cancers, and the favorable overall prognosis associated with conventional Hodgkin Therapy treatments (despite elevated risks of heart disease and second cancers in adulthood) have been barriers to the development of validated biomarkers, however.

Targeted therapies might be another way to sidestep the long-term toxicities from conventional cytotoxic and radiation therapies for childhood cancers, she says.

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Programmed death protein 1 and its ligand (PD-1 and PD-L1), which are the targets of immune checkpoint blockade agents like nivolumab and pembrolizumab, might also be attractive targets and biomarkers for pediatric Hodgkin lymphoma, Kelly said. “Immune checkpoint blockade can help to release the brakes and allow T cells in to destroy the Hodgkin Lymphoma cells.”

Kolb is similarly hopeful that the tools of personalized medicine research can be brought to bear on childhood AML.

Children with Down Syndrome face a particularly high risk of developing AML: a 10- to 20-fold higher incidence of AML overall - and until their fourth birthday, a 500-fold increased incidence of AML, Dr. Kolb said. Children with Down Syndrome tend to develop AML at a younger age (before age 2, on average, versus about age 7 among children who do not have Down Syndrome and are diagnosed with this cancer.

Down Syndrome-associated AML often harbors a gene mutation called GATA1. On its own, GATA1 can cause myeloid dysplasia, but not full-blown AML, suggesting that other mutations are required for leukemia, he noted.

“Mutations in GATA1 are found in nearly all patients with Down Syndrome AML who are diagnosed prior to age 4 years, but are rare in non-Down Syndrome AML and in Down Syndrome AML in children older than 4 years,” he noted.

“Why do kids with Down Syndrome get the GATA1 mutations? I think you have to go back to Trisomy 21,” he said, referring to the chromosomal malformation that causes Down Syndrome itself. It is associated with increased rates of DNA damage elsewhere in the genome, and reduced DNA repair activity in the body’s cells, he noted.

AML in Down Syndrome is more drug-sensitive than other AML cells, he points out.

That allows these children to be treated with less-intensive regimens. “Therapy reduction is the targeted response to Down Syndrome-AML,” concluded Kolb.

“We need to consider targeted strategies - not just targeted therapies,” he said.