title: Serial and quantitative analysis of mixed hematopoietic chimerism by PCR in patients with acute leukemias allows the prediction of relapse after allogeneic BMT.
abstract: Within a prospective study we analyzed hematopoietic chimerism in serial peripheral blood samples taken from 55 patients with acute leukemias (ALL 21, AML 20, MDS 14) with a median age of 13.5 years at very short time intervals following allogeneic bone marrow transplantation (allo-BMT). The investigation was performed to determine the implications of mixed hematopoietic chimerism (MC) with regard to the clinical outcome in patients with acute leukemias after allo-BMT. Analysis of chimerism was performed by PCR of variable number of tandem repeat (VNTR) sequences with a maximum sensitivity of 0.8%. Thirteen male patients transplanted with the marrow of a female donor were also studied by amplification of a Y-chromosome-specific alphoid repeat (0.1-0.01% sensitivity). VNTR analysis in 55 patients revealed complete chimerism (CC) in 36 cases, MC in 18 follow-ups and autologous recovery in one patient. Quantitative analysis of MC identified 10/18 patients with increasing autologous patterns in whom 9/10 subsequently relapsed. The patient with autologous recovery relapsed as well. Eight of 18 patients with MC showed decreasing amounts of autologous DNA and became CC upon further follow-up. In contrast, only 7/36 patients with CC in the prior analysis of chimerism status relapsed. However, in 4/7 patients the interval between last CC confirmation and relapse was more than 4 months. In 2/7 patients autologous DNA was not detectable in peripheral blood but in bone marrow aspirates. One of these seven patients developed a fulminant relapse within 3 weeks. The probability of relapse-free survival for patients with CC is 0.67 (n = 36), for patients with decreasing MC 1.0 (n = 8) and for patients with increasing MC 0.1 (n = 10). In summary, the results demonstrate that serial and quantitative chimerism analysis at short time intervals by PCR provides a reliable and rapid screening method for the early detection of recurrence of underlying disease and is therefore a prognostic tool to identify patients at highest risk of relapse.
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital, Tübingen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Bader
authors.forename: J
authors.initials: J
authors.lastname: Beck
authors.forename: A
authors.initials: A
authors.lastname: Frey
authors.forename: P G
authors.initials: PG
authors.lastname: Schlegel
authors.forename: H
authors.initials: H
authors.lastname: Hebarth
authors.forename: R
authors.initials: R
authors.lastname: Handgretinger
authors.forename: H
authors.initials: H
authors.lastname: Einsele
authors.forename: C
authors.initials: C
authors.lastname: Niemeyer
authors.forename: N
authors.initials: N
authors.lastname: Benda
authors.forename: C
authors.initials: C
authors.lastname: Faul
authors.forename: L
authors.initials: L
authors.lastname: Kanz
authors.forename: D
authors.initials: D
authors.lastname: Niethammer
authors.forename: T
authors.initials: T
authors.lastname: Klingebiel
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation; D005260:Female; D005819:Genetic Markers; D006086:Graft vs Host Disease / Q000235:genetics; D006412:Hematopoietic Stem Cells; D006801:Humans; D007938:Leukemia / Q000628:therapy*; D015470:Leukemia, Myeloid, Acute / Q000628:therapy; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000628:therapy; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011446:Prospective Studies; D012008:Recurrence; D018183:Transplantation Chimera / Q000235:genetics; D014998:Y Chromosome
chemical_list: D005819:Genetic Markers