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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.
Source Information
From the Hospital San Raffaele–Telethon Institute for Gene Therapy (HSR-TIGET) (L.V., M.G.R., K.F.), the Hematology and Bone Marrow Transplantation Unit, Department of Oncology (L.V., S.K.P., M.T.L.S., B.F., M.B., J.P., C. Corti, F.C.), the Cancer Immunotherapy and Gene Therapy Program (S.K.P., M.C., A.B., C. Bonini), Diagnostica e Ricerca (M.Z., N.F.P., M.F.), and the HLA Tissue Typing Laboratory and Immunohematology and Transfusion Medicine Service (B.M., S.R., K.F.), Istituto di Ricovero e Cura a Carattere Scientifico Hospital San Raffaele; the Università Vita-Salute San Raffaele (M.F., M.G.R., C. Bordignon); the Dipartimento di Scienze e Tecnologie Biomediche, Universitá degli Studi di Milano (C. Barlassina, C. Cosentino, F.T.); the Piattaforma Genomica e Bioinformatica, Fondazione Filarete (C. Barlassina, C. Cosentino, F.T.); and MolMed (C. Bordignon) — all in Milan; and Shardna Life Sciences, Pula, Cagliari, Italy (A.A.).
Address reprint requests to Dr. Ciceri at the Hematology and Bone Marrow Transplantation Unit, IRCCS H San Raffaele, via Olgettina 60, 20132 Milan, Italy, or at ciceri.fabio{at}hsr.it.
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