Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation
| Autor: | Liang Zhao, L. Green, T. Dougan, Haesook T. Kim, Christopher D. Gocke, J. Tsuji, Madeleine Duran, Siqing Wang, Amy E. DeZern, Brendan Blumenstiel, Sarah Nikiforow, Richard J. Jones, Niall J. Lennon, Yi-Bin Chen, Mark Fleharty, Christopher J. Gibson, Lukasz P. Gondek, Alana F. Ogata, David R. Walt, Vincent T. Ho, Chi-An Cheng, R. C. Lindsley, Jerome Ritz, Rafael Madero-Marroquin, H. M. Murdock, Joseph H. Antin, Bryan C. Hambley, Robert J. Soiffer, Carrie Cibulskis |
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| Rok vydání: | 2022 |
| Předmět: |
Adult
Male Cancer Research Time Factors Allogeneic transplantation Adolescent Somatic cell medicine.medical_treatment Calcineurin Inhibitors Graft vs Host Disease Germline DNA Methyltransferase 3A Dioxygenases Proinflammatory cytokine Young Adult Recurrence Humans Transplantation Homologous Medicine Child Gene Alleles Aged Leukemia Hematopoietic cell business.industry Clonal hematopoiesis Hematopoietic Stem Cell Transplantation Infant Middle Aged Progression-Free Survival DNA-Binding Proteins Survival Rate Calcineurin Transplantation Haematopoiesis Cytokine Oncology Child Preschool Hematologic Neoplasms Chronic Disease Mutation Immunology Cytokines Female Clonal Hematopoiesis Unrelated Donors business |
| Zdroj: | Journal of Clinical Oncology. 40:189-201 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | PURPOSEClonal 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 METHODSWe 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.RESULTSCH 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.CONCLUSIONDonor 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. |
| Databáze: | OpenAIRE |
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