Patient 2

The second patient was nearly 4 years old at baseline. She was diagnosed with therapy-related AML (t-AML) 6 months after completing treatment for metastatic neuroblastoma.

To treat her neuroblastoma, this patient received induction followed by myeloablative chemotherapy and autologous HSCT. For t-AML treatment, the patient received chemotherapy and allogeneic HSCT.


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Samples were taken at 3 time points: harvest for the autologous HSCT, diagnosis of t-AML, and remission of t-AML prior to allogeneic HSCT.

The t-AML had a higher number of substitution mutations than is normally found in de novo childhood AML, and 93% of these substitutions harbored platinum therapy signatures.

“The t-AML harbored a balanced KMT2A-MLLT1 translocation, commonly attributed

to topoisomerase II inhibitors such as etoposide, which she had received during induction,” Dr Behjati and colleagues wrote.

Variants found at t-AML diagnosis were also found in the autograft and remission samples, with the exception of the KMT2A fusion.

This patient is still alive and in remission 8 years after allogeneic HSCT.

Extension Cohort

Dr Behjati and colleagues analyzed blood from an extension cohort of 18 patients with pediatric cancers. The researchers were also able to analyze tumor samples from 17 of these patients.

The analyses revealed an additional patient, a 4-year-old girl, with evidence of clonal hematopoiesis and platinum signatures after treatment for relapsed neuroblastoma.

The clone had 810 substitutions, 85% of which had platinum signatures. This patient ultimately died from neuroblastoma before any myeloid neoplasm was detected.

For 6 other children in the cohort who had been treated with platinum chemotherapy, no clonal hematopoiesis was detected.

Implications and Next Steps

“We have recognized clonal hematopoiesis as an aging-related phenomenon with a limited set of genes that drive this in adults, but, in this study, the authors do not find these typical drivers in these children,” Dr Rauh said. “Some of the drivers of clonal hematopoiesis in children with cancer have possibly been missed because we’ve been biased and have been looking at the wrong genes.”

Dr Behjati suggested that, in the future, the clonal composition of blood could be analyzed after each chemotherapy cycle or at the end of treatment to detect the presence of any clonal hematopoiesis and assist with clinical and monitoring decisions.

“My hunch is that what is happening is that a lot of children have clonal expansions, and a tiny minority go on and develop leukemia,” Dr Behjati said. “Certainly, our data would be consistent with our proposition because we see both scenarios.”

“With neuroblastoma, we need to figure out how common this is and whether we can correlate the presence of clones with the development of cancer later on in life,” Dr Behjati said. “But there’s also a widely accepted notion that the blood of children who have undergone cancer treatment is normal. I think this needs to be thrown out and needs to be revisited from scratch.”

Reference

Coorens THH, Collord G, Lu W, et al. Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment. Blood. 2021;137(21):2992-2997. doi:10.1182.blood.2020010150