Clonal hematopoiesis of indeterminate potential is rare in pediatric patients undergoing autologous stem cell transplantation

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) describes recurrent somatic gene mutations in the blood of healthy individuals, associated with higher risk for hematological malignancies and higher all-cause mortality by cardiovascular disease. CHIP increases with age and is more common in adult patients after chemotherapy or radiation for cancer. Furthermore, in some adult patients undergoing autologous stem cell transplantation (ASCT) or thereafter, CHIP has been identified. In children and adolescents, it remains unclear how cellular stressors such as cytotoxic therapy influence the incidence and expansion of CHIP. We conducted a retrospective study on 33 pediatric patients mostly with solid tumors undergoing ASCT for presence of CHIP. We analyzed CD34+ selected peripheral blood stem cell grafts after several cycles of chemotherapy, prior to cell infusion, by next-generation sequencing including 18 “CHIP-genes”. Apart from a somatic variant in TP53 in one patient no other variants indicative of CHIP were identified. As a CHIP-unrelated finding, germline variants in CHEK2 and in ATM were identified in two and four patients, respectively. In conclusion, we could not detect “typical” CHIP variants in our cohort of pediatric cancer patients undergoing ASCT. However, more studies with larger patient numbers are necessary to assess if chemotherapy in the pediatric setting contributes to an increased CHIP incidence and at what time point.

Keywords:

• Autologous stem cell transplantation
• cancer
• CHIP
• pediatric

Acknowledgements

We thank the whole team of the stem cell program of the Inselspital Bern for their collaboration in caring for our pediatric patients. In particular, we are grateful to the stem cell laboratory for their collaboration and all colleagues referring patients from all over Switzerland to our center. We also acknowledge the support provided by Prof. Gabriela M. Baerlocher and Claudio Brunhold in supplying samples. We especially thank Friedgard Julmy for her support collecting clinical data. M.K.K. acknowledges funding from the “Nachwuchsfoerderungs-Grant” of the University Hospital Inselspital Berne.

Disclosure statement

M.K.K.: consulting or advisory role: Bayer, SOBI, Takeda, Roche; research funding: NovoNordisk; travel, accommodations, expenses: Bayer, NovoNordisk, SOBI, Takeda.

J.R.: consulting or advisory role: Bayer, Jazz, SOBI, Pierre Fabre; research funding: Novartis, Roche. Currently employee of Novartis Pharma Basel.

The remaining authors (A.K., N.A.P., R.J., C.Z., V.U.B., T.P.) do not have any conflict of interest to declare.

Author contributions

M.K.K., A.K. and J.R. conceived and designed the study. M.K.K., A.K., C.E.K. performed collection of clinical data. R.J. and N.A.P. led the generation and analysis of sequencing data. R.J., N.A.P., C.Z., V.U.B., T.P., J.R. performed analyses and/or participated in data interpretation. All authors contributed to the writing of the manuscript and approved it for submission.

Availability of data and materials

The datasets generated and/or analyzed during the current study are available in the NCBI BioSample repository, [BioSample accessions: SAMN32301637, SAMN32301638, SAMN32301639, SAMN32301640, SAMN32301641, SAMN32301642; Submission ID: SUB12447514] & are available from the corresponding author on reasonable request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.