Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant: Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression

• Authors: David A. Jacobsohn, George Washington University; Michael R. Loken, Hematologics, Inc.; Mingwei Fei, Medical College of Wisconsin; Alexia Adams, Center for International Blood and Marrow Transplant Research; Lisa Eidenschink Brodersen, Hematologics, Inc.; Brent R. Logan, Medical College of Wisconsin; Kwang Woo Ahn, Medical College of Wisconsin; Bronwen E. Shaw, Medical College of Wisconsin; Morris Kletzel, Ann & Robert H Lurie Children's Hospital; Marie Olszewski, Ann & Robert H Lurie Children's Hospital; Sana Khan, Ann & Robert H Lurie Children's Hospital; Soheil Meshinchi, Fred Hutchinson Cancer Research Center; Amy Keating, University of Colorado; Andrew Harris, University of Michigan Health System; Pierre Teira, University of Montreal; Reggie E. Duerst, Ann & Robert H Lurie Children's Hospital; Steven P. Margossian, Dana Farber Cancer Institute; Paul L. Martin, Duke University; Aleksandra Petrovic, Johns Hopkins All Children's Hospital; Ann E Haight, Emory University
• Journal Title: Biology of Blood and Marrow Transplantation
• Volume: Volume 24, Number 10
• Publisher: Elsevier: 12 months | 2018-10-01, Pages 2040-2046
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.bbmt.2018.06.010
• Subjects: Health Sciences, Immunology; Health Sciences, Medicine and Surgery; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Hematology; Immunology; Transplantation; Cytogenetics and molecular genetics; Measurable residual disease; Stem cell transplantation; Laboratory hematology; RELAPSE RISK; WT1; AML; CHILDREN; THERAPY; TARGET; TOOL

Abstract

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a “difference from normal” flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P <.001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.