Clonal hematopoiesis in the donor does not adversely affect long-term outcomes following allogeneic hematopoietic stem cell transplantation: result from a 13-year follow-up

Abstract

Donor clonal hematopoiesis may be transferred to the recipient through allogeneic hematopoietic stem cell transplantation (HCT), but the potential for adverse long-term impact on transplant outcomes remains unknown. A total of 744 samples from 372 recipients who received HCT and the corresponding donors were included. Bar-coded error-corrected sequencing using a modified molecular inversion probe capture protocol was performed, which targeted 34 genes covering mutations involved in clonal hematopoiesis with indeterminate potential (CHIP) and other AML-related mutations. A total of 30 mutations were detected from 25 donors (6.7%): the most frequently mutated gene was TET2 (n=7, 28%), followed by DNMT3A (n=4, 16%), SMC3 (n=3, 12%) and SF3B1 (n=3, 12%). With a median follow-up duration of 13 years among survivors, the presence of CHIP in the donor was not associated with recipient overall survival (p=0.969), relapse incidence (p=0.600) or non-relapse mortality (p=0.570). Donor CHIP did not impair neutrophil (p=0.460) or platelet (p=0.250) engraftment, the rates of acute (p=0.490), or chronic graft-vs-host disease (p=0.220). No significant difference was noted for secondary malignancy following HCT between the two groups. The present study suggests that the presence of CHIP in allogeneic stem donors does not adversely affect transplant outcomes after HCT. Accordingly, further study is warranted to reach a clearer conclusion on whether molecular profiling to determine the presence of CHIP mutations is necessary for the pre-transplant evaluation of donors prior to stem cell donation.

The impact of epigenetic modifications on allogeneic hematopoietic stem cell transplantation

“…Two smaller studies also examined the CHIP-alloreactivity link: A single-center study found increased risk of acute GVHD but not chronic GVHD and no differences in incidence of relapse; notably, this study included a large number of high-risk patients, with over half of the cohort having active disease at the time of transplantation ( 61 ). A more recent study also failed to replicate the results from the larger studies, likely due to the significantly limited sample size (only 25 mutated donor products were identified, with an unusual distribution of CHIP mutations, potentially due to thefact that donors as young as 17 were included) ( 62 ). GVHD following liver transplantation (LT-GVHD) is a rare complication, associated with bone marrow failure and a hyperinflammatory state; in a case series of 9 patients where 7 bone marrow samples were available for next generation sequencing, DNMT3A mutations were found in 5 out of 7 samples, as compared to 1 of 6 in a LT-non-GVHD cohort ( 63 ).…”

“…No recipients with sole mutations in DNMT3A or TET2 developed DCL. Two smaller studies also examined the CHIP-alloreactivity link: A single-center study found increased risk of acute GVHD but not chronic GVHD and no differences in incidence of relapse; notably, this study included a large number of high-risk patients, with over half of the cohort having active disease at the time of transplantation (61). A more recent study also failed to replicate the results from the larger studies, likely due to the significantly limited sample size (only 25 mutated donor products were identified, with an unusual distribution of CHIP mutations, potentially due to thefact that donors as young as 17 were included) (62).…”