Platinum-based chemotherapy appears to cause the clonal hematopoiesis that results in myeloid neoplasms in pediatric patients with neuroblastoma, according to research published in Blood.
These findings, based on an analysis of 20 patients, contrast prior findings in adults with therapy-related myeloid neoplasms.
“Our study is the first to show that platinum treatment leaves imprints and probably directly causes it [the myeloid neoplasms],” said study author Sam Behjati, MD, PhD, of the Wellcome Sanger Institute in Hinxton, United Kingdom.
“It’s not only that these are platinum-associated clonal expansions. It’s actually the platinum treatment causing the clonal expansion, which then is the seed of developing leukemia subsequently,” Dr Behjati added.
“The paradigm now in adult therapy-related myeloid neoplasms is that the therapy selects for clones with pre-existing mutations; it doesn’t create the clones necessarily,” said Michael Rauh, MD, PhD, of Queen’s University and Kingston General Hospital in Ontario, Canada, who was not involved in this study.
“What I think is really exciting about this paper is that it seems to be different in children, where they show that the platinum-based chemotherapy has created mutations that are new in these patients. And then, in some cases, these have expanded,” Dr Rauh added.
For this study, Dr Behjati and colleagues first sequenced samples from 2 pediatric patients with neuroblastoma and then sequenced samples from an additional 18 patients with various pediatric cancers.
The first patient, a 7-year-old girl, developed therapy-related myelodysplastic syndrome (t-MDS) 10 months after completing treatment for neuroblastoma. The treatment consisted of a 7-agent induction regimen, followed by myeloablative chemotherapy and autologous hematopoietic stem cell transplant (HSCT).
Blood or bone marrow samples were taken at 7 time points, including a sample of pretreatment neuroblastoma-infiltrated bone marrow. The researchers used whole-genome sequencing and bioinformatics analyses to reconstruct myeloid neoplasm development.
The major findings were an almost 4-fold higher number of point mutations, compared with the median found in de novo pediatric acute myeloid leukemia (AML), and mutation signatures linked to platinum chemotherapy exposure.
The first evidence of the origin of t-MDS was found during induction chemotherapy, with 78% of mutations found to exhibit platinum chemotherapy signatures. A leukemogenic variant in PTPN11 (G503E)was found in the autograft.
“Of note, the sequence context of the founding PTPN11 driver mutation confers a 99% probability of this lesion arising as a result of platinum mutagenesis,” Dr Behjati and colleagues wrote.
This patient ultimately experienced a neuroblastoma relapse that proved fatal.