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Author Notes:

Michael A. Pulsipher, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112. Phone: 323-361-8840; Fax: 323-361-8068; E-mail:

M.A. Pulsipher: Enrolling and treating patients, gathering data, performing data analysis, interpreting results, writing–original draft, writing–review and editing. X. Han: Performing data analysis, interpreting results, writing–review and editing. S.L. Maude: Enrolling and treating patients, gathering data, writing–review and editing. T.W. Laetsch: Enrolling and treating patients, gathering data, writing–review and editing. M. Qayed: Writing–review and editing. S. Rives: Enrolling and treating patients, gathering data, writing–review and editing. M.W. Boyer: Enrolling and treating patients, gathering data, writing–review and editing. H. Hiramatsu: Enrolling and treating patients, gathering data, writing–review and editing. G.A. Yanik: Enrolling and treating patients, gathering data, writing–review and editing. T. Driscoll: Enrolling and treating patients, gathering data, writing–review and editing. G.D. Myers: Enrolling and treating patients, gathering data, writing–review and editing. P. Bader: Enrolling and treating patients, gathering data, writing–review and editing. A. Baruchel: Enrolling and treating patients, gathering data, writing–review and editing. J. Buechner: Enrolling and treating patients, gathering data, writing–review and editing. H.E. Stefanski: Enrolling and treating patients, gathering data, writing–review and editing. C. Kalfoglou: Writing–review and editing. K. Nguyen: Performing data analysis, interpreting results, writing–review and editing. E.R. Waldron: Performing data analysis, interpreting results, writing–review and editing. K. Thudium Mueller: Writing–review and editing. H.J. Maier: Writing–review and editing. G. Kari: Writing–review and editing. S.A. Grupp: Enrolling and treating patients, gathering data, writing–review and editing.

The studies presented herein were sponsored by Novartis Pharmaceuticals Corporation. The authors sincerely thank the patients enrolled in the ELIANA and ENSIGN studies and their families, as well as the principal investigators, support staff, study site coordinators, data monitoring committee members, and institutional review committee members. The authors also thank Harlan Robins, Paul Fields, and Erik Yusko (all employees of Adaptive Biotechnologies) for their contributions in generating the NGS-MRD data and supporting the interpretation of some aspects of the associated results, as well as David A. James, Lida Pacaud, Andrea Chassot Agostinho, and Chris del Corral. Editorial support was provided by Healthcare Consultancy Group and was funded by Novartis Pharmaceuticals Corporation.

M.A. Pulsipher reports personal fees from Novartis during the conduct of the study, as well as personal fees from Novartis, Jasper Therapeutics, Medexus, Equillium, Bellicum, and Mesoblast, and grants, personal fees, and nonfinancial support from Miltenyi and Adaptive outside the submitted work. X. Han reports nonfinancial support from Healthcare Consultancy Group during the conduct of the study, as well as personal fees from Novartis outside the submitted work. S.L. Maude reports grants and personal fees from Novartis Pharmaceuticals during the conduct of the study, as well as personal fees from Wugen and Kite Pharma outside the submitted work. T.W. Laetsch reports grants, personal fees, and nonfinancial support from Novartis during the conduct of the study, as well as grants from Pfizer, grants and personal fees from Bayer, and personal fees from YmAbs Therapeutics, Cellectis, Deciphera, and Jumo Health outside the submitted work. M. Qayed reports personal fees from Novartis outside the submitted work. S. Rives reports personal fees from Novarits, Kite, Cellectis, and Celgene/Bristol Myers Squibb during the conduct of the study, as well as personal fees from Jazz Pharma and Amgen outside the submitted work. G.D. Myers reports other support from Novartis Pharmaceuticals outside the submitted work. P. Bader reports grants and personal fees from Novartis, personal fees from Amgen, and grants from Bristol Myers Squibb during the conduct of the study; grants from Medac, Neovii, and Riemser outside the submitted work; and a patent for MSC-FFM licensed and with royalties paid from Medac. A. Baruchel reports personal fees and nonfinancial support from Novartis during the conduct of the study, as well as grants and personal fees from Servier, and personal fees from Jazz, Celgene, and Amgen outside the submitted work. J. Buechner reports personal fees, nonfinancial support, and other support from Novartis during the conduct of the study. H.E. Stefanski reports other support from Novartis outside the submitted work. K. Nguyen reports employment with Novartis. E.R. Waldron reports employment with Novartis. K. Thudium Mueller reports other support from Novartis outside the submitted work and was employed with Novartis at the time the work was completed. H.J. Maier reports other support from Novartis outside the submitted work, as well as employment with Novartis Pharma AG, Switzerland. G. Kari reports employment with Novartis. S.A. Grupp reports grants, personal fees, and nonfinancial support from Novartis during the conduct of the study. No disclosures were reported by the other authors.

Subject:

Keywords:

  • Antigens, CD19
  • Child
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Neoplasm, Residual
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Receptors, Antigen, T-Cell
  • Recurrence
  • Young Adult

Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia

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Journal Title:

Blood Cancer Discovery

Volume:

Volume 3, Number 1

Publisher:

, Pages 66-81

Type of Work:

Article | Final Publisher PDF

Abstract:

We assessed minimal residual disease (MRD) detection and B-cell aplasia after tisagenlecleucel therapy for acute lymphoblastic leukemia (ALL) to define biomarkers predictive of relapse (N = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relapse. B-cell recovery [signifying loss of functional chimeric antigen receptor (CAR) T cells] within the first year of treatment was associated with a hazard ratio (HR) for relapse of 4.5 [95% confidence interval (CI), 2.03–9.97; P< 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18–10.8; P < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44–7.69; P = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87–50; P < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33–4.79; P = 0.7). Relapses occurring with persistence of B-cell aplasia were largely CD19− (23/25: 88%). Detectable BMNGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation (HCT) or second CAR-T cell infusion.

Copyright information:

©2021 The Authors; Published by the American Association for Cancer Research

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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