Serial and quantitative analysis of mixed hematopoietic chimerism by PCR in patients with acute leukemias allows the prediction of relapse after allogeneic BMT.
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.
Bader
P
P
Department of Pediatric Hematology/Oncology, University Children's Hospital, Tübingen, Germany.
Beck
J
J
Frey
A
A
Schlegel
P G
PG
Hebarth
H
H
Handgretinger
R
R
Einsele
H
H
Niemeyer
C
C
Benda
N
N
Faul
C
C
Kanz
L
L
Niethammer
D
D
Klingebiel
T
T
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
D005819:Genetic Markers