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Acquired uniparental disomy in chromosome 6p as a feature of relapse after T-cell replete haploidentical hematopoietic stem cell transplantation using cyclophosphamide tolerization

Bone Marrow Transplantation volume 52, pages 615–619 (2017)Cite this article

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Recurrent disease after haploidentical hematopoietic stem cell transplantation (HI HSCT) is a significant obstacle to its success, requiring investigations into mechanisms of relapse to further improve outcomes. Acquired uniparental disomy (aUPD) is a known tumor escape mechanism,1, 2, 3, 4 in which a mitotic recombination event results in the loss of one parental copy of a chromosome or part of a chromosome and the gain of a second copy from the alternate parent. The consequence of this mutation is a loss of heterozygocity in the affected region with preservation of genetic copy number. aUPD potentially contributes to clonal evolution by rendering tumor cells homozygous for a pre-existing oncogenic mutation.5, 6 After HI HSCT, Vago and colleagues7, 8 identified the presence of aUPD in the MHC region of chromosome 6p in leukemic cells in a subset of adult patients with recurrent AML using whole-genome single nucleotide polymorphism (SNP) arrays. aUPD in this region (aUPD-6p) resulted in the loss of the unshared haplotype on the leukemic cells circumventing allogenic recognition and rendering donor lymphocyte infusions (DLI) for post-HSCT relapse ineffective. Active disease at HSCT and a diagnosis of AML have been identified as risk factors for the development of aUPD-6p.9 Evidence that immunological pressure by the donor immune system contributes to the occurrence of post-HSCT aUPD-6p consists of associations between aUPD-6p and specificity to HLA-mismatched HSCT, higher T cell doses in the allogeneic graft, chronic GVHD,9 treatment with DLI10 and lateness of relapse implicating immunological as opposed to conditioning failure to control the disease. Information regarding the development of aUPD-6p as a feature of relapse after a cyclophosphamide (CY)-based HI HSCT is limited. Therefore, we investigated whether this mechanism of relapse was prevalent in patients undergoing a two-step HI HSCT using CY tolerization to inform treatment decisions.

Starting at the end of 2011, patients with a diagnosis of AML who relapsed after HI HSCT using the Jefferson two-step approach were to be assessed for aUPD-6p. The two-step approach has been described elsewhere,11, 12, 13 but briefly after conditioning with 12 Gy total body irradiation (myeloablative) or a fludarabine-based reduced intensity conditioning, patients received a fixed dose of 2 × 108/kg T cells (HSCT step 1) followed 2-days later by CY for bidirectional tolerization. Two days after CY, all patients received a CD34-selected donor product (HSCT step 2). Mycophenolate mofetil and tacrolimus were used as GVHD prophylaxis. The former was discontinued at day +28, a taper of the latter was initiated at day +42 in the absence of active GVHD.

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Authors and Affiliations

  1. Department of Hematological Malignancies and Blood and Marrow Transplantation, Division of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    D Grosso, O Alpdogan, M Carabasi, J Filicko-O'Hara, S Gaballa, M Kasner, T Klumpp, U Martinez-Outschoorn, J L Wagner, M Weiss & N Flomenberg

  2. Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA

    E Johnson & Z Wang

  3. Department of Tissue Typing, Thomas Jefferson University, Philadelphia, PA, USA

    B Colombe

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  1. D Grosso
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  2. E Johnson
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  4. O Alpdogan
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  6. J Filicko-O'Hara
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  9. T Klumpp
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  11. J L Wagner
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Correspondence to D Grosso.

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Grosso, D., Johnson, E., Colombe, B. et al. Acquired uniparental disomy in chromosome 6p as a feature of relapse after T-cell replete haploidentical hematopoietic stem cell transplantation using cyclophosphamide tolerization. Bone Marrow Transplant 52, 615–619 (2017). https://doi.org/10.1038/bmt.2016.324

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