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Case Report: Calpainopathy Presenting After Bone Marrow Transplantation, With Studies of Donor Genetic Content in Various Tissue Types.

ABSTRACT: We present a patient who had two allogeneic bone marrow transplantations for acute lymphocytic leukemia. She developed slowly progressive limb-girdle weakness in the context of other symptoms of graft-vs.-host disease (GVHD). Her myopathy symptoms had been initially attributed to GVHD, but when she progressed despite immunotherapy, genetic testing was requested. Initial testing was performed on a blood sample, identifying a variant of unknown significance in DMD. Subsequent testing of DNA from the patient's muscle tissue identified two pathogenic variants in CAPN3, with absence of the DMD variant (this latter variant presumed to have been received from the donor). Allele-specific digital droplet qPCR permitted the quantification of the donor variant in various tissues from the patient (whole skin, isolated fibroblasts, whole blood, saliva, buccal cells, urine sediment, and two muscle biopsies taken at a 2 year interval). This report emphasizes that genetic disease should still be considered in the context of presumably acquired disease, and also demonstrates the extent of transdifferentiation of donor cells into other tissues.

SUBMITTER: Martens K

PROVIDER: S-EPMC7829329 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Case Report: Calpainopathy Presenting After Bone Marrow Transplantation, With Studies of Donor Genetic Content in Various Tissue Types.

Martens Kristina K Leckie Jamie J Fok Daniel D Wells Robyn A RA Chhibber Sameer S Pfeffer Gerald G

Frontiers in neurology 20210111

We present a patient who had two allogeneic bone marrow transplantations for acute lymphocytic leukemia. She developed slowly progressive limb-girdle weakness in the context of other symptoms of graft-vs.-host disease (GVHD). Her myopathy symptoms had been initially attributed to GVHD, but when she progressed despite immunotherapy, genetic testing was requested. Initial testing was performed on a blood sample, identifying a variant of unknown significance in <i>DMD</i>. Subsequent testing of DNA ...[more]

PMID: 33505349

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Project description:PurposeHematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT.Patients and methodsWe performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy.ResultsNotably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS.ConclusionOur prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

Dataset Information

Case Report: Calpainopathy Presenting After Bone Marrow Transplantation, With Studies of Donor Genetic Content in Various Tissue Types.

Publications

Case Report: Calpainopathy Presenting After Bone Marrow Transplantation, With Studies of Donor Genetic Content in Various Tissue Types.

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