Randomized trial examines purging of tumor cells from stem cells prior to transplantation in neuroblastoma patients

Judith Villablanca, MD, of The Saban Research Institute of Children's Hospital Los Angeles, Susan Kreissman, MD, of Duke University Medical Center, and colleagues reported the results of a randomized, phase 3 clinical trial conducted by the Children's Oncology Group examining the effect of selectively removing (purging) tumor cells from blood stem cells before they are transplanted back into patients with high-risk neuroblastoma following high-dose chemotherapy. This is the first randomized trial looking at the effect of tumor selective stem cell purging on patient outcome. The study will be published online July 25 in the prestigious journal Lancet Oncology.

“This study illustrates the importance of clinical trials developed as a partnership between lab scientists and clinical researchers to create optimal therapies for treating children with cancer. Each successive trial builds on the previous one allowing us to continuously be working on safer and more effective treatments”

Neuroblastoma is the second most common solid tumor in children. Half of all children diagnosed with this condition have high-risk disease, meaning that they are less responsive to treatment and have less than a 50% chance of survival. Standard treatment includes a course of high dose chemotherapy because it is more effective at killing tumor cells, however, it also kills the normal blood-forming cells in the bone marrow. In order to mitigate this effect, some immature blood cells (called peripheral blood stem cells or PBSC) are removed before the child is treated with high dose chemotherapy and then re-infused after treatment. This procedure is called an autologous peripheral blood stem cell transplant.

Since neuroblastoma often spreads into the blood and bone marrow, stem cells collected for transplant may be mixed with tumor cells. It was not known if removing tumor cells from the stem cells would change the outcome for patients. To find out, Robert Seeger, MD, Patrick Reynolds, MD, PhD and their team at Children's Hospital Los Angeles, developed a technique for removing or "purging" the tumor cells from the blood stem cells. This technique involved using antibodies that attached the tumor cells to magnetic beads, and then were removed using strong magnets. Purging stem cells as well as the high dose chemotherapy regimen used in this study were both first piloted in a prior multi-center trial led by Children's Hospital Los Angeles and chaired by Dr. Villablanca.

This multicenter, phase 3 clinical trial randomized patients to receive either purged or non-purged PBSC following high dose chemotherapy. Purging was done, for all patients randomized to that treatment, at a centralized lab at Children's Hospital Los Angeles. The study showed that purging stem cells prior to transplant did not significantly affect patient survival, suggesting that patients had other tumor sites in their body that were not effectively treated by the high dose chemotherapy. This information now allows oncologists to eliminate the complex and expensive purging process. Future investigations will focus on new therapies that are more effective at killing resistant tumor cells throughout the body.

A second important finding from this study was that patient survival was not decreased when total body irradiation (TBI) was eliminated from the treatment regimen. TBI had been used in the previous COG transplant study. Eliminating TBI resulted in the reduction of serious radiation side effects including cataracts, short stature and abnormal tooth development.

"This study illustrates the importance of clinical trials developed as a partnership between lab scientists and clinical researchers to create optimal therapies for treating children with cancer. Each successive trial builds on the previous one allowing us to continuously be working on safer and more effective treatments," says Judith Villablanca, MD, principal investigator at Children's Hospital and Professor of Clinical Pediatrics at the Keck School of Medicine of the University of Southern California.

The extremely sensitive tumor cell detection method called "TLDA" was developed by Robert C. Seeger, MD, Director of the Cancer Research Program at The Saban Research Institute. Tumor cells detected by TLDA in the PBSC prior to purging predicted which patients would have worse outcomes. Testing for tumor using this method may provide a new marker to help identify which patients are less likely to respond to standard therapy and who might benefit from more novel approaches.

"Our new TLDA test, which can be used to test bone marrow, blood, or PBSC during the course of therapy or at the end of all therapy provides an excellent means of assessing the response of the patient's tumor cells to treatment. This response assessment appears to be very helpful in predicting patient outcome," says Robert C. Seeger, MD, who is also Professor of Pediatrics at the Keck School of Medicine of USC.