Loss of mismatched HLA in leukemia after stem-cell transplantation.
BACKGROUND
Transplantation of hematopoietic stem cells from partially matched family donors is a promising therapy for patients who have a hematologic cancer and are at high risk for relapse. The donor T-cell infusions associated with such transplantation can promote post-transplantation immune reconstitution and control residual disease.


METHODS
We identified 43 patients who underwent haploidentical transplantation and infusion of donor T cells for acute myeloid leukemia or myelodysplastic syndrome and conducted post-transplantation studies that included morphologic examination of bone marrow, assessment of hematopoietic chimerism with the use of short-tandem-repeat amplification, and HLA typing. The genomic rearrangements in mutant variants of leukemia were studied with the use of genomic HLA typing, microsatellite mapping, and single-nucleotide-polymorphism arrays. The post-transplantation immune responses against the original cells and the mutated leukemic cells were analyzed with the use of mixed lymphocyte cultures.


RESULTS
In 5 of 17 patients with leukemia relapse after haploidentical transplantation and infusion of donor T cells, we identified mutant variants of the original leukemic cells. In the mutant leukemic cells, the HLA haplotype that differed from the donor's haplotype had been lost because of acquired uniparental disomy of chromosome 6p. T cells from the donor and the patient after transplantation did not recognize the mutant leukemic cells, whereas the original leukemic cells taken at the time of diagnosis were efficiently recognized and killed.


CONCLUSIONS
After transplantation of haploidentical hematopoietic stem cells and infusion of donor T cells, leukemic cells can escape from the donor's antileukemic T cells through the loss of the mismatched HLA haplotype. This event leads to relapse.
Vago
Luca
L
Hospital San Raffaele-Telethon Institute for Gene Therapy, Milan, Italy.
Perna
Serena Kimi
SK
Zanussi
Monica
M
Mazzi
Benedetta
B
Barlassina
Cristina
C
Stanghellini
Maria Teresa Lupo
MT
Perrelli
Nicola Flavio
NF
Cosentino
Cristian
C
Torri
Federica
F
Angius
Andrea
A
Forno
Barbara
B
Casucci
Monica
M
Bernardi
Massimo
M
Peccatori
Jacopo
J
Corti
Consuelo
C
Bondanza
Attilio
A
Ferrari
Maurizio
M
Rossini
Silvano
S
Roncarolo
Maria Grazia
MG
Bordignon
Claudio
C
Bonini
Chiara
C
Ciceri
Fabio
F
Fleischhauer
Katharina
K
D000328:Adult; D002478:Cells, Cultured; D002896:Chromosomes, Human, Pair 6; D020544:Graft vs Leukemia Effect / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008285:Major Histocompatibility Complex; D009154:Mutation; D009190:Myelodysplastic Syndromes; D012008:Recurrence; D012189:Retrospective Studies; D013601:T-Lymphocytes / Q000276:immunology*; D018183:Transplantation Chimera
D006680:HLA Antigens