Loss of mismatched HLA in leukemia after stem-cell transplantation

Luca Vago, Serena Kimi Perna, Monica Zanussi, Benedetta Mazzi, Cristina Barlassina, Maria Teresa Lupo Stanghellini, Nicola Flavio Perrelli, Cristian Cosentino, Federica Torri, Andrea Angius, Barbara Forno, Monica Casucci, Massimo Bernardi, Jacopo Peccatori, Consuelo Corti, Attilio Bondanza, Maurizio Ferrari, Silvano Rossini, Maria Grazia Roncarolo, Claudio Bordignon & 3 others Chiara Bonini, Fabio Ciceri, Katharina Fleischhauer

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)478-488
Number of pages11
JournalNew England Journal of Medicine
Volume361
Issue number5
DOIs
Publication statusPublished - Jul 30 2009

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Stem Cell Transplantation
Leukemia
Tissue Donors
Transplantation
T-Lymphocytes
Haplotypes
Histocompatibility Testing
Hematopoietic Stem Cell Transplantation
Recurrence
Microsatellite Repeats
Uniparental Disomy
Bone Marrow Examination
Chimerism
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Single Nucleotide Polymorphism
Chromosomes
Lymphocytes

ASJC Scopus subject areas

  • Medicine(all)

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Vago, L., Perna, S. K., Zanussi, M., Mazzi, B., Barlassina, C., Stanghellini, M. T. L., ... Fleischhauer, K. (2009). Loss of mismatched HLA in leukemia after stem-cell transplantation. New England Journal of Medicine, 361(5), 478-488. https://doi.org/10.1056/NEJMoa0811036

Loss of mismatched HLA in leukemia after stem-cell transplantation. / Vago, Luca; Perna, Serena Kimi; Zanussi, Monica; Mazzi, Benedetta; Barlassina, Cristina; Stanghellini, Maria Teresa Lupo; Perrelli, Nicola Flavio; Cosentino, Cristian; Torri, Federica; Angius, Andrea; Forno, Barbara; Casucci, Monica; Bernardi, Massimo; Peccatori, Jacopo; Corti, Consuelo; Bondanza, Attilio; Ferrari, Maurizio; Rossini, Silvano; Roncarolo, Maria Grazia; Bordignon, Claudio; Bonini, Chiara; Ciceri, Fabio; Fleischhauer, Katharina.

In: New England Journal of Medicine, Vol. 361, No. 5, 30.07.2009, p. 478-488.

Research output: Contribution to journalArticle

Vago, L, Perna, SK, Zanussi, M, Mazzi, B, Barlassina, C, Stanghellini, MTL, Perrelli, NF, Cosentino, C, Torri, F, Angius, A, Forno, B, Casucci, M, Bernardi, M, Peccatori, J, Corti, C, Bondanza, A, Ferrari, M, Rossini, S, Roncarolo, MG, Bordignon, C, Bonini, C, Ciceri, F & Fleischhauer, K 2009, 'Loss of mismatched HLA in leukemia after stem-cell transplantation', New England Journal of Medicine, vol. 361, no. 5, pp. 478-488. https://doi.org/10.1056/NEJMoa0811036
Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MTL et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. New England Journal of Medicine. 2009 Jul 30;361(5):478-488. https://doi.org/10.1056/NEJMoa0811036
Vago, Luca ; Perna, Serena Kimi ; Zanussi, Monica ; Mazzi, Benedetta ; Barlassina, Cristina ; Stanghellini, Maria Teresa Lupo ; Perrelli, Nicola Flavio ; Cosentino, Cristian ; Torri, Federica ; Angius, Andrea ; Forno, Barbara ; Casucci, Monica ; Bernardi, Massimo ; Peccatori, Jacopo ; Corti, Consuelo ; Bondanza, Attilio ; Ferrari, Maurizio ; Rossini, Silvano ; Roncarolo, Maria Grazia ; Bordignon, Claudio ; Bonini, Chiara ; Ciceri, Fabio ; Fleischhauer, Katharina. / Loss of mismatched HLA in leukemia after stem-cell transplantation. In: New England Journal of Medicine. 2009 ; Vol. 361, No. 5. pp. 478-488.
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AU - Vago, Luca

AU - Perna, Serena Kimi

AU - Zanussi, Monica

AU - Mazzi, Benedetta

AU - Barlassina, Cristina

AU - Stanghellini, Maria Teresa Lupo

AU - Perrelli, Nicola Flavio

AU - Cosentino, Cristian

AU - Torri, Federica

AU - Angius, Andrea

AU - Forno, Barbara

AU - Casucci, Monica

AU - Bernardi, Massimo

AU - Peccatori, Jacopo

AU - Corti, Consuelo

AU - Bondanza, Attilio

AU - Ferrari, Maurizio

AU - Rossini, Silvano

AU - Roncarolo, Maria Grazia

AU - Bordignon, Claudio

AU - Bonini, Chiara

AU - Ciceri, Fabio

AU - Fleischhauer, Katharina

PY - 2009/7/30

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N2 - 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.

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