title: Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia.
abstract: Quantification of minimal residual disease (MRD) following allogeneic hematopoietic cell transplantation (allo-HCT) predicts post-transplant relapse in patients with chronic lymphocytic leukemia (CLL). We utilized an MRD-quantification method that amplifies immunoglobulin heavy chain (IGH) loci using consensus V and J segment primers followed by high-throughput sequencing (HTS), enabling quantification with a detection limit of one CLL cell per million mononuclear cells. Using this IGH-HTS approach, we analyzed MRD patterns in over 400 samples from 40 CLL patients who underwent reduced-intensity allo-HCT. Nine patients relapsed within 12 months post-HCT. Of the 31 patients in remission at 12 months post-HCT, disease-free survival was 86% in patients with MRD <10(-4) and 20% in those with MRD ≥10(-4) (relapse hazard ratio (HR) 9.0; 95% confidence interval (CI) 2.5-32; P<0.0001), with median follow-up of 36 months. Additionally, MRD predicted relapse at other time points, including 9, 18 and 24 months post-HCT. MRD doubling time <12 months with disease burden ≥10(-5) was associated with relapse within 12 months of MRD assessment in 50% of patients, and within 24 months in 90% of patients. This IGH-HTS method may facilitate routine MRD quantification in clinical trials.
authors: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: A C
authors: AC
authors: Logan
authors: B
authors: B
authors: Zhang
authors: B
authors: B
authors: Narasimhan
authors: V
authors: V
authors: Carlton
authors: J
authors: J
authors: Zheng
authors: M
authors: M
authors: Moorhead
authors: M R
authors: MR
authors: Krampf
authors: C D
authors: CD
authors: Jones
authors: A N
authors: AN
authors: Waqar
authors: M
authors: M
authors: Faham
authors: J L
authors: JL
authors: Zehnder
authors: D B
authors: DB
authors: Miklos
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000175:diagnosis* / Q000235:genetics*; D011379:Prognosis; D012008:Recurrence; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D007143:Immunoglobulin Heavy Chains