Modulation of Radiation Biomarkers in a Randomized Phase II Study of I-MIBG With or Without Radiation Sensitizers for Relapsed or Refractory Neuroblastoma.

Susan Groshen, Kevin Campbell, Angela C Evans, Stephen Wilson, Aimy Sebastian, Gabriela G Loots, Araz Marachelian, Myriam Armant, Sharmistha Pal, Daphne A Haas-Kogan, Julie R Park, Meaghan Granger, Katherine K Matthay, Matthew A Coleman, Steven G DuBois

Journal: International journal of radiation oncology, biology, physics 2023;115(5):1115-1128

PMID: 36526235

Full Text on Elsevier Science View on PubMed

Abstract

PURPOSE

I-metaiodobenzylguanidine (I-MIBG) has demonstrated efficacy as a single agent in neuroblastoma. Recent trials have focused on I-MIBG combination strategies, though little is known about the effect of putative radiosensitizers on biological markers of radiation exposure.

METHODS AND MATERIALS

NANT2011-01 evaluated I-MIBG therapy alone (arm A) or in combination with vincristine/irinotecan (arm B) or vorinostat (arm C) for patients with relapsed or refractory neuroblastoma. Blood samples were collected before and after I-MIBG infusion to determine levels of radiation-associated biomarkers (transcript and protein). The association of biomarker with treatment arm, clinical response, and treatment toxicity was analyzed.

RESULTS

The cohort included 99 patients who had at least 1 biomarker available for analysis. Significant modulation in most biomarkers between baseline, 72, and 96 hours following I-MIBG was observed. Patients in arm C had the lowest degree of modulation in FLT3 ligand protein. Lower baseline BCL2 transcript levels were associated with higher overall response. Patients with greater increases in FLT3 ligand at 96 hours after I-MIBG therapy were significantly more likely to have grade 4 thrombocytopenia. Peripheral blood gene expression of the BCL2 family of apoptotic markers (BCL2L1 and BAX transcripts) was significantly associated with grade 4 hematologic toxicity. RNA sequencing demonstrated little overlap in the top modulated peripheral blood transcripts between randomized arms.

CONCLUSIONS

Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after I-MIBG and concomitant radiation sensitizers affect extent of modulation. Biomarkers related to hematopoietic damage and apoptosis were associated with hematologic toxicity.

Address: Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California; Department of Radiation Oncology, University of California, Davis School of Medicine, Sacramento, California.; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California.; Children's Hospital of Los Angeles, Los Angeles, California.; Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.; Hematology and Oncology Center, Cook Children's Medical Center, Fort Worth, Texas.; Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts. Electronic address: [email protected].

DOI: 10.1016/j.ijrobp.2022.11.045