Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes.
Pubmed ID: 37276081
Pubmed Central ID: PMC10448421
Journal: Blood advances
Publication Date: Aug. 22, 2023
MeSH Terms: Humans, Alleles, Hematopoietic Stem Cell Transplantation, Allogeneic Cells, Cell-Free Nucleic Acids, Clone Cells, Neoplasm, Residual
Grants: R01 HL156144, R21 HL143096
Authors: Varadhan R, Wang S, Pasca S, Guo MZ, Stokvis K, Shedeck A, Pallavajjala A, Shams C, Pallavajjala R, DeZern AE, Gocke CD, Jones RJ, Gondek LP
Cite As: Pasca S, Guo MZ, Wang S, Stokvis K, Shedeck A, Pallavajjala A, Shams C, Pallavajjala R, DeZern AE, Varadhan R, Gocke CD, Jones RJ, Gondek LP. Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes. Blood Adv 2023 Aug 22;7(16):4660-4670.
Studies:
- Blood and Marrow Clinical Trials Network (BMT CTN) A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (0402)
- Blood and Marrow Clinical Trials Network (BMT CTN) Comparing Peripheral Blood Stem Cell Transplantation Versus Bone Marrow Transplantation in Individuals With Hematologic Cancers (0201)
Abstract
The measurable residual disease (MRD) assessment provides an attractive predictor of allogeneic hematopoietic cell transplnat (alloHCT) outcomes. Cell-free DNA (cfDNA) has been applied to diagnosis, early detection, and disease burden monitoring in various tumors, but its utility as an MRD test in myeloid malignancies has not been systematically evaluated. We sought to determine the differential sensitivity between bone marrow (BM) and cfDNA MRD and to assess the effect of cfDNA MRD on alloHCT outcomes. The technical and clinical validation cohorts, including 82 patients participating in clinical trials (Bone Marrow Transplant Clinical Trials Network-0201 and 0402), were used. Ultradeep error-corrected targeted sequencing was performed on plasma and BM-derived DNA. We demonstrated that 94.6% (range, 93.9-95.3) of cfDNA was derived from hematopoietic tissue. The mutant allele fraction was congruent between BM and cfDNA (rho = 0.8; P < .0001); however, cfDNA seemed to be more sensitive in detecting clones with a variant allele frequency (VAF) of <0.26%. cfDNA-MRD clearance by day 90 after alloHCT (D90) was associated with improved relapse-free survival (RFS, median survival not reached vs 5.5 months; P < .0001) and overall survival (OS, median survival not reached vs 7.3 months; P < .0001) when compared with patients with persistent MRD. Irrespective of pre-alloHCT MRD, D90 cfDNA MRD was associated with inferior 2-year OS (16.7% vs 84.8%; P < .0001) and RFS (16.7% vs 80.7%; P < .0001). cfDNA seems to be an accurate, minimally invasive alternative to BM aspirates in MRD assessment and confers important prognostic implications in patients with myeloid malignancies undergoing alloHCT.