Frontiers in Neuroblastoma Treatment

Dr. Jacqueline Kraveka and child assistant examine a doll.
Dr. Jacqueline Kraveka with patient Victoria Thompson, who is enrolled in the first upfront pediatric precision medicine trial in neuroblastoma. Photograph by Sarah Pack

MUSC Children's Health is conducting pioneering clinical trials on upfront precision medicine therapy and relapse prevention for neuroblastoma

by Vitria Adisetiyo

Beat Childhood Cancer (BCC), a national clinical trials consortium,1 is sponsoring two multicenter phase 2 trials on advanced treatments for high-risk neuroblastoma. As part of BCC, MUSC Hollings Cancer Center will serve as a site for both trials, each led by Jacqueline M. Kraveka, D.O., a pediatric hematologist-oncologist at MUSC Children’s Health.

Neuroblastoma is a solid extracranial cancerous tumor that develops from improperly matured nerve cells. With 700 cases diagnosed annually in the U.S., neuroblastoma is the most common cancer in infants and the third cause of childhood death from cancer.2Neuroblastoma has diverse clinical presentations and outcomes. Patients are stratified into low, intermediate or high risk for recurrence. While non–high-risk patients have a survival rate of more than 90 percent, the survival rate for the 40 percent of patients who are high-risk is less than 50 percent.

Standard upfront (initial) therapy for high-risk neuroblastoma typically consists of induction (six cycles of chemotherapy, with stem cell collection after cycle two), surgical resection of tumors, consolidation (stem cell transplant to restore bone marrow), radiation of residual tumors and maintenance (retinoic acid therapy to help cells mature and anti-Ganglioside GD2 immunotherapy to eradiacte minimal residual disease by targeting the GD-2 positive neuroblastoma cells). Unfortunately, up to 20 percent of patients do not respond to induction and at least half of all high-risk patients will relapse during or after maintenance.2

“The issue is how to improve these outcomes,” says Kraveka. “One way would be to add a targeted agent during induction to improve response rate — this is the front-end approach of the Pediatric Precision Laboratory Advanced Neuroblastoma (PEDS-PLAN) trial (NCT02559778). Another way would be to prevent relapse — this is the back-end approach of the PEDS-PLAN and Neuroblastoma Maintenance Therapy (NMTT; NCT02679144) trials.”

The PEDS-PLAN trial is the first to incorporate precision medicine into upfront therapy for newly diagnosed high-risk neuroblastoma. This study uses a novel, molecular-guided therapy protocol established in a previous BCC clinical trial in relapsed patients that demonstrated safety and feasibility. For each patient, tumor, and blood samples are collected to generate a genomic report that identifies genetic mutations (via DNA exomes) and altered molecular pathways (via RNA sequencing) in the cancer. An algorithm identifies known drugs that target these features and predicts the best drug to add to upfront therapy (during cycles three through six of induction). An interdisciplinary molecular tumor board then reviews the report and the scientific literature and decides on the patient’s treatment.

“Most personalized medicine studies only look for one specific genetic mutation and offer one targeted agent. Consequently, these studies find a match for only 25 percent of cases,” explains Kraveka. “By including RNA sequencing and bioinformatics, we’ve come up with a precision medicine plan that includes six possible drugs for all patients.”

Another novel arm of the PEDS-PLAN trial is the addition of difluromethylornithine (DFMO) to maintenance as a strategy to prevent recurrence. DFMO is a low-cost and readily available oral drug developed to treat African sleeping sickness but is also being studied for high-risk neuroblastoma. As an inhibitor of a cell growth enzyme associated with the MYCN oncogene (overexpressed in high-risk tumors), DFMO has been used to prevent recurrence in relapsed patients.3 In the PEDS-PLAN trial, patients are given DFMO for two years in the remission setting. Administration of DFMO is randomized to start at the beginning or end of immunotherapy. Twenty patients have been enrolled, and early findings show no reports of toxicity.

“Preventing relapse is key. After immunotherapy, there’s nothing we can do for prevention in standard care,” says Kraveka. “Once someone relapses, neuroblastoma is very difficult to cure, but there are a lot of things we can still do.”

For patients who received upfront therapy outside of the PEDS-PLAN trial, the NMTT trial is another way they can receive DFMO during remission. In a recently completed component of this trial (enrolling 139 patients), the two-year event-free survival rate was 84 percent for those receiving DFMO after standard upfront therapy and 52 percent for those receiving DFMO during remission after relapse. Mild elevation of liver function enzymes was the only side effect. The NMTT trial will next expand enrollment to patients who completed non-standard upfront therapy and refractory patients who are in remission after additional therapy.

Kraveka is taking patient referrals for both trials until 2025, and there are no additional costs to patients. The studies cover genomic screening and DFMO, while insurance covers standard treatments.

“There hasn’t been any treatment in the past that achieved this level of survival,” says Kraveka. “Kids are able to go to school and DFMO is well tolerated. It’s been really exciting to be able to offer these treatments to our patients.”


1 Beat Childhood Cancer. 2017.

2 Whittle SB, et al. Expert Rev Anticancer Ther. 2017 Apr;17(4):369-386.

3 Saulnier Sholler GL, et al. PLoS One. 2015 May 27;10(5):e0127246.