title: Real-time assessment of relapse risk based on the WT1 marker in acute leukemia and myelodysplastic syndrome patients after hematopoietic cell transplantation.
abstract: Relapse is the major cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT) for acute leukemia and myelodysplastic syndrome (MDS). Wilms' tumor Ag (WT1) is overexpressed in the majority of acute leukemia and MDS patients and has been proposed as a universal diagnostic marker for detection of impending relapse. Comprehensive studies have shown that WT1 transcript levels have predictive value in acute leukemia patients in CR after chemotherapy. However, the focus of this study is the period after alloHCT for predicting relapse onset. We analyzed the accumulation of WT1 mRNA transcripts in PB of 82 leukemia and MDS patients and defined specific molecular ratios for relapse prediction. The extensively validated WT1/c-ABL ratio was used to normalize increases in WT1 transcript levels. The observed lead time of crossing or exceeding set WT1 levels is presented along with linear interpolation to estimate the calculated day the WT1 thresholds were crossed. The WT1/c-ABL transcript ratio of 50 or above yielded 100% specificity and 75% sensitivity reliably predicting future relapse with an observed average of 29.4 days (s.d.=19.8) and a calculated average of 63 days (s.d.=29.3) lead time before morphologic confirmation. A lower ratio of 20 or above gave lower specificity, but higher sensitivity (84.8% and 87.5%, respectively) identified more patients who relapsed, at earlier times, providing an earlier warning with actual average lead time of 49.1 days (s.d.=30.8) and calculated average of 78 days (s.d.=28.8). WT1 transcript levels serve as a diagnostic relapse test with greater sensitivity than the morphologic approach used in the clinic as a readout.
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Israyelyan
authors.affiliation: Division of Biostatistics, Department of Information Sciences, Duarte, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Goldstein
authors.affiliation: Department of Hematology/Hematopoietic Cell Transplantation, Duarte, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Tsai
authors.affiliation: Clinical Trials Office, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Aquino
authors.affiliation: Department of Hematology/Hematopoietic Cell Transplantation, Duarte, CA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Department of Hematology/Hematopoietic Cell Transplantation, Duarte, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D064591:Allografts; D014408:Biomarkers, Tumor / Q000097:blood*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000175:diagnosis / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000175:diagnosis / Q000628:therapy; D016315:Proto-Oncogene Proteins c-abl / Q000097:blood; D012333:RNA, Messenger / Q000097:blood*; D012334:RNA, Neoplasm / Q000097:blood*; D012008:Recurrence; D012307:Risk Factors; D013997:Time Factors; D025721:WT1 Proteins / Q000097:blood*
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025721:WT1 Proteins; C583751:WT1 protein, human; D016315:Proto-Oncogene Proteins c-abl