Engrafted Donor-Derived Clonal Hematopoiesis after Allogenic Hematopoietic Cell Transplantation is Associated with Chronic Graft-versus-Host Disease Requiring Immunosuppressive Therapy, but no Adverse Impact on Overall Survival or Relapse

Newell, Laura F.; Williams, Todd; Liu, James H.; Yu, Yun; Chen, Yiyi; Booth, G.; Knight, R.K.; Goslee, K.; Cook, Rachel J.; Leonard, Jessica; Meyers, Gabrielle; Traer, Elie; Press, Richard D.; Fan, Guang; Wang, Ying; Raess, Philipp W.; Maziarz, Richard T.; Dunlap, Jennifer

doi:10.1016/j.jtct.2021.04.014

Cited by 22 publications

(6 citation statements)

References 36 publications

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“…Given that Gibson et al found a positive correlation between DNMT3A variants on relapse-free survival after HSCT in general [ 8 ], this may explain why the indicated case of DCL arose after a long latency of almost 10 years. Consistent with previous publications, we do not believe that the concomitant DNMT3A variant had a causal (negative) impact on DCL pathogenesis [ 8 , 10 ].…”

supporting

confidence: 89%

DDX41 germline variants causing donor cell leukemia indicate a need for further genetic workup in the context of hematopoietic stem cell transplantation

et al. 2023

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supporting

confidence: 89%

DDX41 germline variants causing donor cell leukemia indicate a need for further genetic workup in the context of hematopoietic stem cell transplantation

et al. 2023

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“…11 Exploratory studies have found that CH in transplant donors can engraft in recipients [12][13][14][15] but have reported conflicting results on the impact of donor CH on transplant-specific clinical outcomes, graft immunologic function, and risk of donor cell leukemia (DCL). 12,13,16,17 These studies have been limited by modest sample sizes that affected outcomes analysis, cohort characteristics that restricted generalizability, and a lack of mechanistic rationale. Furthermore, these cohorts have not parsed the clinical impact of different CH mutations or used sequencing technologies that support evaluation of low-abundance clones, which could have unique dynamics in the context of allogeneic transplantation.…”

Section: Introductionmentioning

confidence: 99%

Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation

Gibson

Kim

Zhao

et al. 2022

JCO

115

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PURPOSE Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain. PATIENTS AND METHODS We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant. RESULTS CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction ≥ 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations. CONCLUSION Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome–associated mutations or germline predisposition in donors.

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“… 8 reported no difference in cGvHD incidence between the two groups, similar to our result, with no impact of donor CHIP on relapse risk. In another study by Newell et al ., 32 donor-derived CHIP was not associated with relapse or OS; however, patients with donor-derived CHIP were more likely to develop cGvHD, necessitating systemic immunosuppressive therapy (IST) ( P =0.045) and less likely to discontinue IST ( P =0.03) compared with controls without donor-derived CHIP. Thus, the differential impact of donor CHIP on relapse risk may not be directly from a putative biological CHIP-related protection from relapse but may instead be related to the occurrence of GvHD, which can indirectly affect the risk of relapse.…”

Section: Discussionmentioning

confidence: 99%

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

Kim

Novitzky‐Basso

et al. 2023

haematol

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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.

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Engrafted Donor-Derived Clonal Hematopoiesis after Allogenic Hematopoietic Cell Transplantation is Associated with Chronic Graft-versus-Host Disease Requiring Immunosuppressive Therapy, but no Adverse Impact on Overall Survival or Relapse

Cited by 22 publications

References 36 publications

DDX41 germline variants causing donor cell leukemia indicate a need for further genetic workup in the context of hematopoietic stem cell transplantation

DDX41 germline variants causing donor cell leukemia indicate a need for further genetic workup in the context of hematopoietic stem cell transplantation

Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation

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

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