Evaluation of clonal hematopoiesis in pediatric ADA-SCID gene therapy participants

Abstract

Autologous stem cell transplant with gene therapy (ASCT-GT) provides curative therapy while reducing pretransplant immune-suppressive conditioning and eliminating posttransplant immune suppression. Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase and telomere lengths (TLs) shorten with natural aging and DNA damaging processes. It is possible that, if CHIP is present before ASCT-GT or mutagenesis occurs after busulfan exposure, the hematopoietic stem cells carrying these somatic variants may survive the conditioning chemotherapy and have a selective reconstitution advantage, increasing the risk of hematologic malignancy and overall mortality. Seventy-four peripheral blood samples (ranging from baseline to 120 months after ASCT-GT) from 10 pediatric participants who underwent ASCT-GT for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) after reduced-intensity conditioning with busulfan and 16 healthy controls were analyzed for TL and CHIP. One participant had a significant decrease in TL. There were no CHIP-associated mutations identified by the next-generation sequencing in any of the ADA-SCID participants. This suggests that further studies are needed to determine the utility of germline analyses in revealing the underlying genetic risk of malignancy in participants who undergo gene therapy. Although these results are promising, larger scale studies are needed to corroborate the effect of ASCT-GT on TL and CHIP. This trial was registered at www.clinicaltrials.gov as #NCT00794508.

Figure 1.

Linear regression analysis of TL measurements. Relative TL (T/S ratio), an estimated concentration of the telomere DNA (T) repeats divided by the single-copy (S) hemoglobin gene in participant 401, forced through baseline time point (ranging from baseline to 80 months after GT) (A); participant 402 forced through baseline time point (ranging from baseline to 120 months after GT) (B); participant 403 (ranging from 5 to 118 months after GT) (C); participant 404 forced through baseline time point (ranging from baseline to 96 months after GT) (D); participant 405 intercept forced through baseline time point (ranging from baseline to 96 months after GT) (E); participant 406 (ranging from 6 to 72 months after GT) (F); participant 407 (ranging from 10 to 96 months after GT) (G); participant 408 forced through baseline time point (ranging from 1 to 84 months after GT) (H); participant 409 (ranging from baseline to 84 months after GT) (I); participant 410 (ranging from 6 to 54 months after GT) (J); and unpaired t test of TLs in 16 controls and all time points (ranging from baseline to 120 months after GT) in patients with ADA-SCID (K). Dotted lines represent 95% confidence bands of the best-fit line (only for those patients without a forced baseline intercept). P-values calculated to represent significant slope deviation from 0.