title: IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients.
abstract: Positive detection of minimal residual disease (MRD) by multichannel flow cytometry (MFC) prior to hematopoietic cell transplantation (HCT) of patients with acute lymphoblastic leukemia (ALL) identifies patients at high risk for relapse, but many pre-HCT MFC-MRD negative patients also relapse, and the predictive power MFC-MRD early post-HCT is poor. To test whether the increased sensitivity of next-generation sequencing (NGS)-MRD better identifies pre- and post-HCT relapse risk, we performed immunoglobulin heavy chain (IgH) variable, diversity, and joining (V[D]J) DNA sequences J NGS-MRD on 56 patients with B-cell ALL enrolled in Children's Oncology Group trial ASCT0431. NGS-MRD predicted relapse and survival more accurately than MFC-MRD (P < .0001), especially in the MRD negative cohort (relapse, 0% vs 16%; P = .02; 2-year overall survival, 96% vs 77%; P = .003). Post-HCT NGS-MRD detection was better at predicting relapse than MFC-MRD (P < .0001), especially early after HCT (day 30 MFC-MRD positive relapse rate, 35%; NGS-MRD positive relapse rate, 67%; P = .004). Any post-HCT NGS positivity resulted in an increase in relapse risk by multivariate analysis (hazard ratio, 7.7; P = .05). Absence of detectable IgH-V(D)J NGS-MRD pre-HCT defines good-risk patients potentially eligible for less intense treatment approaches. Post-HCT NGS-MRD is highly predictive of relapse and survival, suggesting a role for this technique in defining patients early who would be eligible for post-HCT interventions. The trial was registered at www.clinicaltrials.gov as #NCT00382109.
authors: Division of Hematology and Hematological Malignancies, Huntsman Cancer Institute/University of Utah School of Medicine, Primary Children's Hospital, Salt Lake City, UT;
authors: Michael A
authors: MA
authors: Pulsipher
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Adaptive Biotechnologies, Seattle, WA;
authors: Chris
authors: C
authors: Carlson
authors: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA;
authors: Bryan
authors: B
authors: Langholz
authors: Manitoba Blood and Marrow Transplant Program, Winnipeg, MB, Canada;
authors: Donna A
authors: DA
authors: Wall
authors: Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada;
authors: Kirk R
authors: KR
authors: Schultz
authors: Division of Oncology, Children's Hospital of Philadelphia, and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors: Nancy
authors: N
authors: Bunin
authors: Adaptive Biotechnologies, Seattle, WA;
authors: Ilan
authors: I
authors: Kirsch
authors: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH; Department of Pathology and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH;
authors: Julie M
authors: JM
authors: Gastier-Foster
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD;
authors: Michael
authors: M
authors: Borowitz
authors: Adaptive Biotechnologies, Seattle, WA;
authors: Cindy
authors: C
authors: Desmarais
authors: Adaptive Biotechnologies, Seattle, WA;
authors: David
authors: D
authors: Williamson
authors: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and.
authors: Michael
authors: M
authors: Kalos
authors: Division of Oncology, Children's Hospital of Philadelphia, and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Pathology, Children's Hospital of Philadelphia, and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Stephan A
authors: SA
authors: Grupp
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007223:Infant; D008297:Male; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D012008:Recurrence; D012307:Risk Factors; D014184:Transplantation, Homologous; D050441:VDJ Exons / Q000235:genetics*; D055815:Young Adult
chemical_list: D007143:Immunoglobulin Heavy Chains