IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients

• Published in: Blood Vol. 125; no. 22; pp. 3501 - 3508
• Main Authors: Pulsipher, Michael A., Carlson, Chris, Langholz, Bryan, Wall, Donna A., Schultz, Kirk R., Bunin, Nancy, Kirsch, Ilan, Gastier-Foster, Julie M., Borowitz, Michael, Desmarais, Cindy, Williamson, David, Kalos, Michael, Grupp, Stephan A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.05.2015; American Society of Hematology
• Subjects: Adolescent; Adult; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; High-Throughput Nucleotide Sequencing; Humans; Immunoglobulin Heavy Chains - genetics; Infant; Male; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Prognosis; Recurrence; Risk Factors; Transplantation; Transplantation, Homologous; VDJ Exons - genetics; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-12-615757

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. •IgH-V(D)J NGS-MRD detection pretransplant identifies a cohort at low risk for relapse, for which treatment modification could be considered.•Positive NGS-MRD was highly predictive of relapse and survival as early as 30 days after HCT.