Although current treatments can cure 80 to 90 percent of cases, acute lymphoblastic leukemia (ALL) remains the second leading cause of cancer deaths in children. Patients with a resistant form of the disease, who relapse following successful treatment or who have other high risk features have few treatment options. Acute myeloid leukemia (AML) is also difficult to treat in children.
In a first-of-its-kind study, investigators at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center are testing precision cancer medicine in children and young adults with relapsed or high-risk leukemias. The goal is to determine whether powerful next-generation DNA sequencing can spot mutations or genetic changes in leukemia cells that can be targeted by cancer drugs.
“We are searching for alterations in genes to find out if we can match them with a targeted therapy,” explains Yana Pikman, MD, a specialist in pediatric cancer at Dana-Farber/Boston Children’s and principal investigator for the trial.
Personalized medicine for childhood cancer
The study is part of an ongoing effort to improve outcomes by integrating new treatments, such as designer drugs that target overactive growth proteins and molecular pathways in these diseases, with standard chemotherapy. Targeted drugs may also have fewer toxic side effects in young patients.
While next-generation sequencing and matching drugs with genetic alterations has been deployed in research on solid tumors in children, the new trial is the first to examine the feasibility of this approach in childhood leukemias, Pikman says. While the National Cancer Institute MATCH trial is giving targeted therapy to “match” specific genetic alterations in both adults and children, it excludes patients with leukemia.
In the trial Pikman is leading,Dana-Farber and eight other cancer centers will provide patient samples that will be analyzed at the Center for Advanced Molecular Pathology at Brigham and Women’s Hospital using the Rapid-Heme Panel (RHP). Developed at Dana-Farber/Brigham and Women’s Cancer Center, RHP is a next-generation sequencing platform that examines 95 genes in which alterations have been linked to blood disorders, including leukemia, and can report findings within a week.
Seeking actionable mutations
Each patient’s RHP results will be interpreted by a tumor board of experts who identify which mutations are potentially “actionable” — that is, can be matched to a drug known to counter those alterations. The patient’s treating physician will then be sent a list of potentially effective drugs, which may be in pre-clinical development, available as part of a clinical trial or approved for use.
In some cases, children may have difficulty receiving the drugs recommended by the RHP analysis. For example, some targeted drugs approved for adult leukemia patients may not have a safe pediatric dose established or may not be available in a liquid form for a young child. “The information from this study might help persuade the Food and Drug Administration and the pharmaceutical industry to make these agents available and inform future clinical trials,” notes Pikman.
A customized animal model, called a patient-derived xenograft (PDX) model, will be created for every patient in the study. A sample of the patient’s leukemia will be implanted into an immune-deficient mouse, where it will grow and develop with the genetic characteristics of his or her cancer. For patients who cannot receive the recommended drug, the PDX model allows researchers to rapidly test a series of targeted drugs with no risk to the patient. The model can thus indicate whether the recommended drug or drugs would have been successful had the patient been able to receive them. The models can also provide material for future research.
The two-year trial aims to enroll 100 children and young adults a year, in two categories: patients with leukemia that has relapsed or did not respond to the initial therapy, and patients with newly diagnosed high-risk leukemia, such as AML or ALL, that has a poor prognosis because of certain abnormal features.
Learn more about leukemia treatment at Dana-Farber/Boston Children’s.