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

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 ( = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relap...

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Published in:Blood cancer discovery 2022-01, Vol.3 (1), p.66-81, Article 66
Main Authors: Pulsipher, Michael A, Han, Xia, Maude, Shannon L, Laetsch, Theodore W, Qayed, Muna, Rives, Susana, Boyer, Michael W, Hiramatsu, Hidefumi, Yanik, Gregory A, Driscoll, Tim, Myers, G Doug, Bader, Peter, Baruchel, Andre, Buechner, Jochen, Stefanski, Heather E, Kalfoglou, Creton, Nguyen, Kevin, Waldron, Edward R, Thudium Mueller, Karen, Maier, Harald J, Kari, Gabor, Grupp, Stephan A
Format: Article
Language:English
Subjects:
Antigens, CD19
Child
High-Throughput Nucleotide Sequencing
Humans
Neoplasm, Residual - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis
Receptors, Antigen, T-Cell
Recurrence
Young Adult
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Summary: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 ( = 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; < 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18-10.8; < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44-7.69; = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87-50; < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33-4.79; = 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. SIGNIFICANCE: Detectable disease by BMNGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from HCT or investigational cell therapies. . .
ISSN:2643-3230
2643-3249
DOI:10.1158/2643-3230.bcd-21-0095